CXCR4/CXCL12 mediate autocrine cell- cycle progression in NF1-associated malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.

On the engulfment of antifreeze proteins by ice.

Antifreeze proteins (AFPs) are remarkable biomolecules that suppress ice formation at trace concentrations. To inhibit ice growth, AFPs must not only bind to ice crystals, but also resist engulfment by ice. The highest supercooling, [Formula: see text], for which AFPs are able to resist engulfment is widely believed to scale as the inverse of the separation, [Formula: see text], between bound AFPs, whereas its dependence on the molecular characteristics of the AFP remains poorly understood. By using specialized molecular simulations and interfacial thermodynamics, here, we show that in contrast with conventional wisdom, [Formula: see text] scales as [Formula: see text] and not as [Formula: see text]. We further show that [Formula: see text] is proportional to AFP size and that diverse naturally occurring AFPs are optimal at resisting engulfment by ice. By facilitating the development of AFP structure-function relationships, we hope that our findings will pave the way for the rational design of AFPs.

Learning the relationship between nanoscale chemical patterning and hydrophobicity.

The hydrophobicity of proteins and similar surfaces, which display chemical heterogeneity at the nanoscale, drives countless aqueous interactions and assemblies. However, predicting how surface chemical patterning influences hydrophobicity remains a challenge. Here, we address this challenge by using molecular simulations and machine learning to characterize and model the hydrophobicity of a diverse library of patterned surfaces, spanning a wide range of sizes, shapes, and chemical compositions. We find that simple models, based only on polar content, are inaccurate, whereas complex neural network models are accurate but challenging to interpret. However, by systematically incorporating chemical correlations between surface groups into our models, we are able to construct a series of minimal models of hydrophobicity, which are both accurate and interpretable. Our models highlight that the number of proximal polar groups is a key determinant of hydrophobicity and that polar neighbors enhance hydrophobicity. Although our minimal models are trained on particular patch size and shape, their interpretability enables us to generalize them to rectangular patches of all shapes and sizes. We also demonstrate how our models can be used to predict hot-spot locations with the largest marginal contributions to hydrophobicity and to design chemical patterns that have a fixed polar content but vary widely in their hydrophobicity. Our data-driven models and the principles they furnish for modulating hydrophobicity could facilitate the design of novel materials and engineered proteins with stronger interactions or enhanced solubilities.

Identifying hydrophobic protein patches to inform protein interaction interfaces.

Interactions between proteins lie at the heart of numerous biological processes and are essential for the proper functioning of the cell. Although the importance of hydrophobic residues in driving protein interactions is universally accepted, a characterization of protein hydrophobicity, which informs its interactions, has remained elusive. The challenge lies in capturing the collective response of the protein hydration waters to the nanoscale chemical and topographical protein patterns, which determine protein hydrophobicity. To address this challenge, here, we employ specialized molecular simulations wherein water molecules are systematically displaced from the protein hydration shell; by identifying protein regions that relinquish their waters more readily than others, we are then able to uncover the most hydrophobic protein patches. Surprisingly, such patches contain a large fraction of polar/charged atoms and have chemical compositions that are similar to the more hydrophilic protein patches. Importantly, we also find a striking correspondence between the most hydrophobic protein patches and regions that mediate protein interactions. Our work thus establishes a computational framework for characterizing the emergent hydrophobicity of amphiphilic solutes, such as proteins, which display nanoscale heterogeneity, and for uncovering their interaction interfaces.

Multiplexed Shortwave Infrared Imaging Highlights Anatomical Structures in Mice.

Multiplexed fluorescence in vivo imaging remains challenging due to the attenuation and scattering of visible and traditional near infrared (NIR-I, 650 - 950 nm) wavelengths. Fluorescence imaging using short-wave infrared (SWIR, 1000 - 1700 nm, a.k.a. NIR-II) light enables deeper tissue penetration due to reduced tissue scattering as well as minimal background autofluorescence. SWIR-emitting semiconductor quantum dots (QDs) with tunable emission peaks and optical stability are powerful contrast agents, yet few imaging demonstrations exclusively use SWIR emission beyond two-color imaging schemes. In this study, we engineered three high quality lead sulfide/cadmium sulfide (PbS/CdS) core/shell QDs with distinct SWIR emission ranging from 1100 - 1550 nm for simultaneous three-color imaging in mice. We first use the exceptional photostability of QDs to non-invasively track lymphatic drainage with longitudinal imaging, highlighting the detailed networks of lymphatic vessels with widefield imaging over a 2 hr period. We then perform multiplexed imaging with all three QDs to distinctly visualize the lymphatic system and spatially overlapping vasculature networks, including clearly distinguishing the liver and spleen. This work establishes optimized SWIR QDs for next-generation multiplexed and longitudinal preclinical imaging, unlocking numerous opportunities for preclinical studies of disease progression, drug biodistribution, and cell trafficking dynamics in living organisms.

Accumulation of Antifreeze Proteins on Ice Is Determined by Adsorption.

Antifreeze proteins (AFPs) facilitate the survival of diverse organisms in frigid environments by adsorbing to ice crystals and suppressing their growth. The rate of AFP accumulation on ice is determined by an interplay between AFP diffusion from the bulk solution to the ice-water interface and the subsequent adsorption of AFPs to the interface. To interrogate the relative importance of these two processes, here, we combine nonequilibrium fluorescence experiments with a reaction-diffusion model. We find that as diverse AFPs accumulate on ice, their concentration in the aqueous solution does not develop a gradient but remains equal to its bulk concentration throughout our experiments. These findings lead us to conclude that AFP accumulation on ice crystals, which are smaller than 100 µm in radius, is not limited by the diffusion of AFPs, but by the kinetics of AFP adsorption. Our results imply that mass transport limitations do not hinder AFPs from performing their biological function.

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140.

BACKGROUND: SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), suggesting a role in inflammation. RESULTS: We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. CONCLUSIONS: This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Machine learning classification of multiple sclerosis in children using optical coherence tomography.

BACKGROUND: In children, multiple sclerosis (MS) is the ultimate diagnosis in only 1/5 to 1/3 of cases after a first episode of central nervous system (CNS) demyelination. As the visual pathway is frequently affected in MS and other CNS demyelinating disorders (DDs), structural retinal imaging such as optical coherence tomography (OCT) can be used to differentiate MS. OBJECTIVE: This study aimed to investigate the utility of machine learning (ML) based on OCT features to identify distinct structural retinal features in children with DDs. METHODS: This study included 512 eyes from 187 (neyes = 374) children with demyelinating diseases and 69 (neyes = 138) controls. Input features of the analysis comprised of 24 auto-segmented OCT features. RESULTS: Random Forest classifier with recursive feature elimination yielded the highest predictive values and identified DDs with 75% and MS with 80% accuracy, while multiclass distinction between MS and monophasic DD was performed with 64% accuracy. A set of eight retinal features were identified as the most important features in this classification. CONCLUSION: This study demonstrates that ML based on OCT features can be used to support a diagnosis of MS in children.

Correction: Characterizing surface wetting and interfacial properties using enhanced sampling (SWIPES).

Correction for 'Characterizing surface wetting and interfacial properties using enhanced sampling (SWIPES)' by Hao Jiang et al., Soft Matter, 2019, 15, 860-869, DOI: .

Catheter-directed Thrombolysis for Neonatal IVC and Bilateral Renal Vein Thrombosis: A Case Report.

Renal vein thrombosis is the most common non-catheter-associated venous thromboembolism event in neonates, accounting for up to 20% of cases. Although mortality rates are lower than a variety of other forms of pediatric thrombosis, renal vein thrombi are associated with significant short-term and long-term sequelae. This report presents the case of a full-term neonate presenting with bilateral renal vein thrombosis with inferior vena cava involvement treated with catheter-directed thrombolysis. This case report intends to highlight the value of a multidisciplinary approach to pediatric venous thromboembolism and to outline relevant procedural details and current laboratory and imaging monitoring of catheter-directed thrombolysis.

Antibiotics in Dentoalveolar Surgery, a Closer Look at Infection, Alveolar Osteitis and Adverse Drug Reaction.

PURPOSE: To execute an evidence-based review answering the following questions: "What antibiotic type and mode of delivery are most effective at reducing inflammatory complications in third molar and dental implant surgery? What are the types and rates of antibiotic-related adverse reactions in the context of third molar surgery, infective endocarditis, medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN)?" MATERIAL AND METHODS: We performed a comprehensive literature review of peer-reviewed studies using MEDLINE/PubMed, Cochrane, Scopus/Elsevier, Google Scholar, and Wiley online library databases. RESULTS: Twenty-five studies were reviewed for third molar surgery. Although there is some evidence that systemic antibiotics reduce inflammatory complications (infection and alveolar osteitis), routine use is not recommended for third molar surgery. For at-risk cases, a single preoperative dose of amoxicillin is preferred. Clindamycin, amoxicillin-clavulanic acid and erythromycin have a high adverse risk profile. Eight studies were reviewed for dental implant surgery. Antibiotics with dental implant placement showed little reduction in post surgery infection and minimal improvement in long-term success. A comprehensive search found limited data on antibiotic-related adverse effects in the context of infective endocarditis, MRONJ and ORN. CONCLUSIONS: A set of clinical recommendations are presented to better guide evidence-based and standardized antibiotic usage on the basis of the literature discussed in this review. This review highlights the need for further research focusing on antibiotic type and timing of delivery with adverse drug reaction as a primary outcome measure when assessing treatment outcomes and complications in dentoalveolar surgery. This will better elucidate the risks vs benefits of antibiotic in dentoalveolar surgery.

Disassembly of Nanospheres with a PEG Shell upon Adsorption onto PEGylated Substrates.

Polymeric nanospheres have the ability to encapsulate drugs and are therefore widely used in drug delivery applications. Structural transformations that affect drug release from nanospheres are governed by the surrounding environment. To understand these effects, we investigated the adsorption behavior of three types of nanospheres onto model surfaces using quartz crystal microbalance with dissipation (QCM-D) and by atomic force microscopy (AFM). Substrates were prepared from polymers with different degrees of PEGylation (0, 1, and 15%). Nanospheres were prepared via self-assembly of block copolymers. Tyrosine-derived nanospheres are A-B-A triblock copolymers with methoxy poly(ethylene glycol) (PEG) as the A-blocks and an alternating copolymer of desaminotyrosyl-tyrosine octyl ester and suberic acid oligo(DTO-SA) as the B-block. On non-PEGylated substrates, these nanospheres assembled into a close-packed structure; on PEGylated substrates, the adsorbed nanospheres formed a continuous film, thinner than the size of the nanospheres suggesting unraveling of the PEG corona and disassembly of the nanospheres. Also, the adsorption was concentration-dependent, the final thickness being attained at exponentially longer times at lower concentrations. Such substrate- and concentration-dependent behavior was not observed with Pluronic F-127 and PEG-poly(caprolactone) (PCL) nanospheres. Since the essential difference among the three nanospheres is the composition of the core, we conclude that the core influences the adsorption characteristics of the nanospheres as a consequence of their disassembly upon adsorption. These results are expected to be useful in designing nanospheres for their efficient transport across vascular barriers and for delivering drugs to their targets.

Yttrium-90 Radioembolization in the Office-Based Lab.

PURPOSE: To evaluate the feasibility and benefits of performing yttrium-90 radioembolization in an office-based lab (OBL) compared to a hospital setting. MATERIALS AND METHODS: A radioembolization program was established in March 2019 in an OBL that is managed by the radiology department of a tertiary care center. Mapping and treatment angiograms performed in the OBL from March 2019 through January 2020 were compared to mapping and treatment angiograms performed in the hospital during the same time period. RESULTS: One hundred seventy-six mapping and treatment angiograms were evaluated. There was no difference in the proportion of mapping versus treatment angiograms performed at each site, the proportion of lobar versus selective dose vial administrations, or the mean number of dose vials administered per treatment procedure. Procedure start delays were longer in the hospital than in the OBL (28.6 minutes vs 0.8 minutes; P < .0001), particularly for procedures that were not scheduled as the first case of the day (hospital later case delay, 38.8 minutes vs OBL later case delay, 0.5 minutes; P < .0001). Procedures performed in the hospital took longer on average than procedures performed in the OBL (2 hours, 1.8 minutes vs 1 hour, 44.4 minutes; P = .0004), particularly for procedures that were not scheduled as the first case of the day (hospital later case duration, 2 hours, 7.4 minutes vs OBL later case duration, 1 hour, 43 minutes; P = .0006). CONCLUSIONS: Establishing a radioembolization program within an OBL is feasible and might provide more efficient procedure scheduling than the hospital setting.

Comparative Analysis of Safety and Efficacy of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma in Patients with and without Pre-Existing Transjugular Intrahepatic Portosystemic Shunts.

PURPOSE: To compare the safety and efficacy of transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with and without transjugular intrahepatic portosystemic shunts (TIPS). MATERIALS AND METHODS: This single-institution study included a retrospective review of 50 patients who underwent transarterial chemoembolization for HCC between January 2010 and April 2017. Twenty-five patients had preexisting TIPS, and 25 patients were selected to control for age, sex, and target tumor size. Baseline median Model for End-Stage Liver Disease (MELD; 13 TIPS, 9 control; P < .001) and albumin-bilirubin (ALBI; 3 TIPS, 2 control; P < .001) differed between groups. Safety was assessed on the basis of Common Terminology Criteria for Adverse Events (CTCAE) and change in MELD and ALBI grade assessed between 3 and 6 months. Efficacy was assessed by tumor response and time to progression (TTP). RESULTS: There was 1 severe adverse event (CTCAE grade >2) in the TIPS group. There was no difference in the change in MELD or ALBI grade. Although there was no difference in tumor response (P = .19), more patients achieved a complete response in the control group (19/25, 76%) than in the TIPS group (13/25, 52%). There was no difference in TTP (P = .82). At 1 year, 2 patients in the control group and 3 patients in the TIPS group received a liver transplant. Seven patients died in the TIPS group. CONCLUSIONS: Transarterial chemoembolization is as safe and effective in patients with TIPS as in patients without TIPS, despite worse baseline liver function. Severe adverse events are rare and may be transient.

Hydrophobicity of proteins and nanostructured solutes is governed by topographical and chemical context.

Hydrophobic interactions drive many important biomolecular self-assembly phenomena. However, characterizing hydrophobicity at the nanoscale has remained a challenge due to its nontrivial dependence on the chemistry and topography of biomolecular surfaces. Here we use molecular simulations coupled with enhanced sampling methods to systematically displace water molecules from the hydration shells of nanostructured solutes and calculate the free energetics of interfacial water density fluctuations, which quantify the extent of solute-water adhesion, and therefore solute hydrophobicity. In particular, we characterize the hydrophobicity of curved graphene sheets, self-assembled monolayers (SAMs) with chemical patterns, and mutants of the protein hydrophobin-II. We find that water density fluctuations are enhanced near concave nonpolar surfaces compared with those near flat or convex ones, suggesting that concave surfaces are more hydrophobic. We also find that patterned SAMs and protein mutants, having the same number of nonpolar and polar sites but different geometrical arrangements, can display significantly different strengths of adhesion with water. Specifically, hydroxyl groups reduce the hydrophobicity of methyl-terminated SAMs most effectively not when they are clustered together but when they are separated by one methyl group. Hydrophobin-II mutants show that a charged amino acid reduces the hydrophobicity of a large nonpolar patch when placed at its center, rather than at its edge. Our results highlight the power of water density fluctuations-based measures to characterize the hydrophobicity of nanoscale surfaces and caution against the use of additive approximations, such as the commonly used surface area models or hydropathy scales for characterizing biomolecular hydrophobicity and the associated driving forces of assembly.

Protein Hydration Waters Are Susceptible to Unfavorable Perturbations.

The interactions of a protein, its phase behavior, and, ultimately, its ability to function are all influenced by the interactions between the protein and its hydration waters. Here, we study proteins with a variety of sizes, shapes, chemistries, and biological functions and characterize their interactions with their hydration waters using molecular simulations and enhanced sampling techniques. We find that, akin to extended hydrophobic surfaces, proteins situate their hydration waters at the edge of a dewetting transition, making them susceptible to unfavorable perturbations. We also find that the strength of the unfavorable potential needed to trigger dewetting is roughly the same for all proteins studied here and depends primarily on the width of the hydration shell being perturbed. Our findings establish a framework for systematically classifying protein patches according to how favorably they interact with water.

Characterizing surface wetting and interfacial properties using enhanced sampling (SWIPES).

We introduce an accurate and efficient method for characterizing surface wetting and interfacial properties, such as the contact angle made by a liquid droplet on a solid surface, and the vapor-liquid surface tension of a fluid. The method makes use of molecular simulations in conjunction with the indirect umbrella sampling technique to systematically wet the surface and estimate the corresponding free energy. To illustrate the method, we study the wetting of a family of Lennard-Jones surfaces by water. For surfaces with a wide range of attractions for water, we estimate contact angles using our method, and compare them with contact angles obtained using droplet shapes. Notably, our method is able to capture the transition from partial to complete wetting as surface-water attractions are increased. Moreover, the method is straightforward to implement and is computationally efficient, providing accurate contact angle estimates in roughly 5 nanoseconds of simulation time.

Transcatheter Dialysis Conduit Procedures: Changing National and State-Level Medicare Use Patterns over 15 Years.

PURPOSE: To evaluate the changing use of transcatheter hemodialysis conduit procedures. METHODS: Multiple Centers for Medicare & Medicaid Services datasets were used to assess hemodialysis conduit angiography. Use was normalized per 100,000 beneficiaries and stratified by specialty and site of service. RESULTS: From 2001 to 2015, hemodialysis angiography use increased from 385 to 1,045 per 100,000 beneficiaries (compound annual growth rate [CAGR], +7.4%)]. Thrombectomy use increased from 114 to 168 (CAGR, +2.8%). Angiography and thrombectomy changed, by specialty, +1.5% and -1.3% for radiologists, +18.4% and +14.4% for surgeons, and +24.0% and +17.7% for nephrologists, respectively. By site, angiography and thrombectomy changed +29.1% and +20.7% for office settings and +0.8% and -2.4% for hospital settings, respectively. Radiologists' angiography and thrombectomy market shares decreased from 81.5% to 37.0% and from 84.2% to 47.3%, respectively. Angiography use showed the greatest growth for nephrologists in the office (from 5 to 265) and the greatest decline for radiologists in the hospital (299 to 205). Across states in 2015, there was marked variation in the use of angiography (0 [Wyoming] to 1173 [Georgia]) and thrombectomy (0 [6 states] to 275 [Rhode Island]). Radiologists' angiography and thrombectomy market shares decreased in 48 and 31 states, respectively, in some instances dramatically (eg, angiography in Nevada from 100.0% to 6.7%). CONCLUSIONS: Dialysis conduit angiography use has grown substantially, more so than thrombectomy. This growth has been accompanied by a drastic market shift from radiologists in hospitals to nephrologists and surgeons in offices. Despite wide geographic variability nationally, radiologist market share has declined in most states.

A Descriptive Revenue Analysis of a Wound-Center IR Collaboration to Treat Lower Extremity Venous Ulcers.

PURPOSE: To describe the revenue from a collaboration between a dedicated wound care center and an interventional radiology (IR) practice for venous leg ulcer (VLU) management at a tertiary care center. MATERIALS AND METHODS: This retrospective study included 36 patients with VLU referred from a wound care center to an IR division during the 10-month active study period (April 2017 to January 2018) with a 6-month surveillance period (January 2018 to June 2018). A total of 15 patients underwent endovascular therapy (intervention group), whereas 21 patients did not (nonintervention group). Work relative value units (wRVUs) and dollar revenue were calculated using the Centers for Medicare and Medicaid Services Physician Fee Schedule. RESULTS: Three sources of revenue were identified: evaluation and management (E&M), diagnostic imaging, and procedures. The pathway generated 518.15 wRVUs, translating to $37,522. Procedures contributed the most revenue (342.27 wRVUs, $18,042), followed by E&M (124.23 wRVUs, $8,881), and diagnostic imaging (51.65 wRVUs, $10,599). Intervention patients accounted for 86.7% of wRVUs (449.48) and 80.0% of the revenue ($30,010). An average of 33 minutes (38.3 hours total) and 2.06 hours (36.8 hours total) were spent on E&M visits and procedures, respectively. CONCLUSIONS: In this collaboration between the wound center and IR undertaken to treat VLU, IR and E&M visits generated revenue and enabled procedural and downstream imaging revenue.

Spontaneous recovery of superhydrophobicity on nanotextured surfaces.

Rough or textured hydrophobic surfaces are dubbed "superhydrophobic" due to their numerous desirable properties, such as water repellency and interfacial slip. Superhydrophobicity stems from an aversion of water for the hydrophobic surface texture, so that a water droplet in the superhydrophobic "Cassie state" contacts only the tips of the rough surface. However, superhydrophobicity is remarkably fragile and can break down due to the wetting of the surface texture to yield the "Wenzel state" under various conditions, such as elevated pressures or droplet impact. Moreover, due to large energetic barriers that impede the reverse transition (dewetting), this breakdown in superhydrophobicity is widely believed to be irreversible. Using molecular simulations in conjunction with enhanced sampling techniques, here we show that on surfaces with nanoscale texture, water density fluctuations can lead to a reduction in the free energetic barriers to dewetting by circumventing the classical dewetting pathways. In particular, the fluctuation-mediated dewetting pathway involves a number of transitions between distinct dewetted morphologies, with each transition lowering the resistance to dewetting. Importantly, an understanding of the mechanistic pathways to dewetting and their dependence on pressure allows us to augment the surface texture design, so that the barriers to dewetting are eliminated altogether and the Wenzel state becomes unstable at ambient conditions. Such robust surfaces, which defy classical expectations and can spontaneously recover their superhydrophobicity, could have widespread importance, from underwater operation to phase-change heat transfer applications.