Chemo- and Regioselective Functionalization of Isotactic Polypropylene: A Mechanistic and Structure-Property Study.

Polyolefins represent a high-volume class of polymers prized for their attractive thermomechanical properties, but the lack of chemical functionality on polyolefins makes them inadequate for many high-performance engineering applications. We report a metal-free postpolymerization modification approach to impart functionality onto branched polyolefins without the deleterious chain-coupling or chain-scission side reactions inherent to previous methods. The identification of conditions for thermally initiated polyolefin C-H functionalization combined with the development of new reagents enabled the addition of xanthates, trithiocarbonates, and dithiocarbamates to a variety of commercially available branched polyolefins. Systematic experimental and kinetic studies led to a mechanistic hypothesis that facilitated the rational design of reagents and reaction conditions for the thermally initiated C-H xanthylation of isotactic polypropylene (iPP) within a twin-screw extruder. A structure-property study showed that the functionalized iPP adheres to polar surfaces twice as strongly as commercial iPP while demonstrating similar tensile properties. The fundamental understanding of the elementary steps in amidyl radical-mediated polyolefin functionalization provided herein reveals key structure-reactivity relationships for the design of improved reagents, while the demonstration of chemoselective and scalable iPP functionalization to realize a material with improved adhesion properties indicates the translational potential of this method.

C-H Functionalization of Commodity Polymers.

Synthetic manipulation of polymer substrates is one of the oldest and most reliable methods to increase the functional diversity of soft materials. Modifying the chemical structure of polymers that are already produced on a commodity scale leverages the current high-volume and low-cost production of commodity plastics for the discovery of modern materials. A myriad of polymer C-H functionalization methods have been developed which enable the modification of material properties on both a laboratory and industrial scale. More recently, driven by advances in C-H activation, photoredox catalysis, and radical chemistry, chemoselective approaches have emerged as a means to impart precise functionality onto commodity polymer substrates. This Review discusses the historical significance of and contemporary advances in the C-H functionalization of commodity polymers. The conceptual approach outlined herein presents exciting new directions for the field, including increasing the value of otherwise pervasive materials, uncovering entirely new material properties, and a viable path to upcycle post-consumer plastic waste.

Baseline FeNO Independently Predicts the Dupilumab Response in Patients With Moderate-to-Severe Asthma.

BACKGROUND: FeNO may have a role as both a prognostic and predictive biomarker in combination with eosinophils for assessing responsiveness to some biological therapies. OBJECTIVE: We evaluated the value of baseline FeNO, adjusted for baseline blood eosinophil levels and other clinical characteristics, as an independent predictor of treatment response to dupilumab in patients with uncontrolled moderate-to-severe asthma. METHODS: We performed a post hoc analysis of LIBERTY ASTHMA QUEST (NCT02414854), a phase 3, double-blind study in patients aged 12 years and older with uncontrolled moderate-to-severe asthma, who received dupilumab 200 or 300 mg, or placebo every 2 weeks up to 52 weeks. We assessed the annualized event rate of severe exacerbations and least-squares mean change from baseline in prebronchodilator FEV1 at weeks 12 and 52 in relationship to baseline FeNO, adjusted for eosinophils and other clinical characteristics. RESULTS: The annualized event rate increased with increasing baseline FeNO in placebo and decreased in dupilumab groups. The relative risk of severe exacerbations was 22·7%, 58·3%, and 69·3% lower for dupilumab versus placebo for the FeNO less than 25, 25 to less than 50, and 50 and greater parts per billion subgroups. The magnitude of FEV1 improvement increased with higher baseline FeNO for dupilumab and was consistent across the continuum of FeNO levels in placebo. Both findings were independent of blood eosinophil levels. Significant differences were observed between FeNO subgroups. CONCLUSIONS: Increased baseline FeNO was associated with greater clinical effects in dupilumab versus placebo independently of eosinophil levels and other clinical characteristics.

Toward quantifying the electrostatic transduction mechanism in carbon nanotube molecular sensors.

Despite the great promise of carbon nanotube field-effect transistors (CNT FETs) for applications in chemical and biochemical detection, a quantitative understanding of sensor responses is lacking. To explore the role of electrostatics in sensor transduction, experiments were conducted with a set of highly similar compounds designed to adsorb onto the CNT FET via a pyrene linker group and take on a set of known charge states under ambient conditions. Acidic and basic species were observed to induce threshold voltage shifts of opposite sign, consistent with gating of the CNT FET by local charges due to protonation or deprotonation of the pyrene compounds by interfacial water. The magnitude of the gate voltage shift was controlled by the distance between the charged group and the CNT. Additionally, functionalization with an uncharged pyrene compound showed a threshold shift ascribed to its molecular dipole moment. This work illustrates a method for producing CNT FETs with controlled values of the turnoff gate voltage, and more generally, these results will inform the development of quantitative models for the response of CNT FET chemical and biochemical sensors.

Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.

BACKGROUND: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials. OBJECTIVE: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis. METHODS: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/µL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented. RESULTS: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/µL; week 4: 515-578 cells/µL), CRSwNP (baseline: 440-448 cells/µL; week 16: 595 cells/µL), and atopic dermatitis (baseline: 434-600 cells/µL; week 4: 410-710 cells/µL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/µL; week 4: 230 cells/µL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy. CONCLUSIONS: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.

Discrimination of methylcytosine from hydroxymethylcytosine in DNA molecules.

Modified DNA bases are widespread in biology. 5-Methylcytosine (mC) is a predominant epigenetic marker in higher eukaryotes involved in gene regulation, development, aging, cancer, and disease. Recently, 5-hydroxymethylcytosine (hmC) was identified in mammalian brain tissue and stem cells. However, most of the currently available assays cannot distinguish mC from hmC in DNA fragments. We investigate here the physical properties of DNA with modified cytosines, in efforts to develop a physical tool that distinguishes mC from hmC in DNA fragments. Molecular dynamics simulations reveal that polar cytosine modifications affect internal base pair dynamics, while experimental evidence suggest a correlation between the modified cytosine's polarity, DNA flexibility, and duplex stability. On the basis of these physical differences, solid-state nanopores can rapidly discriminate among DNA fragments with mC or hmC modification by sampling a few hundred molecules in the solution. Further, the relative proportion of hmC in the sample can be determined from the electronic signature of the intact DNA fragment.

Computational study of a nanobiosensor: a single-walled carbon nanotube functionalized with the coxsackie-adenovirus receptor.

Combining single-walled carbon nanotubes (CNT) with biological molecules provides a route to novel nanoscale materials with many promising applications in nanotechnology and nanomedicine. Recent experiments show that CNTs covalently functionalized with the coxsackie-adenovirus receptor (CAR) serve as biosensors capable of specifically recognizing Knob proteins from the adenovirus capsid. These experiments suggest that CAR retains its biologically active form when bound to CNT, but a detailed understanding of the structural changes that occur within CAR after CNT attachment is lacking. To address this, we have performed all-atom classical molecular dynamics (MD) simulations of CAR and the CAR-Knob complex in aqueous solution alone and also when covalently linked to CNT. The MD results show that the CNT damps structural fluctuations in CAR and reduces the internal mobility of the protein. However, CNT induces very little structural deformation and does not affect CAR's ability to specifically bind Knob. This MD study verifies that CAR retains its biological functionality when attached to CNT and provides a computational approach to rationalize nanobiosensing devices.

Primary diffuse large B-cell lymphoma of the dura mater and cranial vault. Case report and literature review.

Primary high-grade lymphoma of the dura mater and cranial vault has rarely been reported. The authors treated a 61-year-old man who presented with a slow-growing scalp mass that involved the cranial vertex. Magnetic resonance imaging revealed an oval mass of the dural type with peripheral edema in the bilateral parietal region, with attachment to the cranial vault and extension to the subgaleal space. After subtotal resection, pathological examination yielded a diagnosis of malignant large B-cell lymphoma. Twenty-three months postoperatively, after undergoing radiation therapy and chemotherapy, the patient is neurologically intact and without systemic dissemination of the malignancy. This is a case of primary malignant B-cell lymphoma of the dura mater with extensive involvement of the skull, which is a very rare event. Imaging-based diagnosis and combined therapy consisting of surgery, radiation therapy, and chemotherapy for the disease are discussed, and the literature on extraaxial malignant lymphomas is extensively reviewed.

Contralateral prophylactic mastectomy: clinical and pathological features from a prospective database.

INTRODUCTION: In keeping with recently documented national trends, a significant and increasing number of patients will have chosen contralateral prophylactic mastectomy (CPM) based on personal preference, without traditional clinical or pathological indication. METHODS: Women who underwent CPM at the University of Louisville from 2003 to 2009 were selected for this study. Descriptive factors were evaluated such as age, race, family history of breast cancer, laterality, hormone receptor status, stage, grade and histology of the index breast lesion. Statistical analysis was used to compute predictive factors for occult contralateral pathology. RESULTS: A total of 107 patients underwent CPM and had adequate medical information to be included in this study. The median age was 48 years, with 88% being white and 12% being African American. Seventy-six percent of the index breast cancers were infiltrating ductal carcinoma and 12% were infiltrating lobular carcinoma. Five "significant" occult pathologies were found in the prophylactically removed breast. Two of the lesions were ductal carcinoma in situ, 2 were lobular carcinoma in situ and 1 was an invasive mucinous carcinoma. On bivariate analysis, there were no factors identified predictive for occult contralateral pathology. CONCLUSIONS: In line with previously reported data, we noted that fewer than 5% of patients who underwent CPM had pathology in the contralateral breast. We were unable to correlate any clinical or pathological characteristics in women who presented with contralateral breast cancer. This study raises serious questions regarding the clinical utility of CPM in detecting synchronous clinically and radiographically occult contralateral primaries.

Interfraction accumulation of seroma during accelerated partial breast irradiation: preliminary results of a prospective study.

PURPOSE: To quantify and characterize the process of seroma accumulation during accelerated partial breast irradiation using multicatheter balloon brachytherapy. MATERIALS AND METHODS: Twenty-two patients were treated using the Contura Multilumen brachytherapy catheter to a dose of 34Gy in 10 fractions over 5 treatment days. Serial aspirations of the vacuum port of the catheter were performed at the time of CT simulation and before each treatment. Volume and characteristics of fluid drawn were recorded. Univariate analysis was performed to evaluate various factors predictive of seroma formation. RESULTS: Median patient age was 59.5 years, body mass index was 31, and volume of surgical specimen was 62.4cm(3). Median time from breast conservation surgery to placement of Contura catheter was 18.5 days. Pericatheter seroma, typically scant with a median volume of 0.75mL, was noted in 91% of patients at CT simulation. A total of 203 aspirations were performed with a median-aspirated seroma volume of 4.05mL. There was no significant correlation between the volume of seroma and histology (invasive vs. in situ), quadrant of location, body mass index, reexcision or reoperation, days from breast conservation surgery to balloon placement, or the volume of specimen removed. Radiation treatment factors, including balloon volume, balloon to skin distance, and planning target volume evaluation, also did not correlate with aspirated seroma. CONCLUSIONS: Interfraction seroma accumulation has a variable pattern of development with no discernible predictors of occurrence. Routine pretreatment aspirations via vacuum port may potentially improve dosimetric reproducibility for a minority of patients.

Free energy landscape of a DNA-carbon nanotube hybrid using replica exchange molecular dynamics.

The DNA-carbon nanotube hybrid (DNA-CN) consists of a single-wall carbon nanotube (SWCN) coated with a self-assembled monolayer of single-stranded DNA (ssDNA). Recent experiments have demonstrated that this nanomaterial is ideal for numerous nanotechnological applications. Despite this importance, the structure of this material remains poorly understood. Molecular dynamics (MD) simulations have provided information about the self-assembly mechanisms and ssDNA conformations that characterize DNA-CN. However, MD simulations of biopolymers at low temperatures (T approximately 300 K) result in kinetic trapping that limits conformational sampling. Here, we present results of a large-scale replica exchange molecular dynamics (REMD) simulation that provides extensive sampling of the entire ensemble of oligonucleotide conformations in a (GT)(7)-SWCN hybrid. We calculate the free energy landscape and find minima corresponding to six distinct conformations, with a nonhelical loop structure as the global minimum. The hybrid contains significant structural disorder, with desorbed bases as an important structural feature. These results expand our understanding of DNA-CN and indicate the relevance of REMD for explorations of the physical properties of organic-inorganic multifunctional nanomaterials.

Probing the structure of DNA-carbon nanotube hybrids with molecular dynamics.

DNA-carbon nanotube hybrids (DNA-CN) are novel nanoscale materials that consist of single-wall carbon nanotubes (SWCN) coated with a self-assembled monolayer of single-stranded DNA (ssDNA). Recent experiments on DNA-CN have shown that this material offers a remarkable set of technologically useful properties such as facilitation of SWCN sorting, chemical sensing, and detection of DNA hybridization. Despite the importance of DNA-CN, a detailed understanding of its microscopic structure and physical properties is lacking. To address this, we have performed classical all-atom molecular dynamics (MD) simulations exploring the self-assembly mechanisms, structure, and energetic properties of this nanomaterial. MD reveals that SWCN induces ssDNA to undergo a spontaneous conformational change that enables the hybrid to self-assemble via the pi-pi stacking interaction between ssDNA bases and SWCN sidewall. ssDNA is observed to spontaneously wrap about SWCN into compact right- or left-handed helices within a few nanoseconds. Helical wrapping is driven by electrostatic and torsional interactions within the sugar-phosphate backbone that result in ssDNA wrapping from the 3' end to the 5' end.

Stereotactic aspiration-thrombolysis of intracerebral hemorrhage and its impact on perihematoma brain edema.

BACKGROUND: Recent reports suggest that when thrombolytic agents are administered within the clot, lysis rate accelerates at the expense of increased risk of worsening edema. To test this hypothesis, we report on the volumetric analysis of (1) the intraparenchymal hematoma and, (2) perihematomal edema in a cohort of ICH patients treated with intraclot rtPA. METHODS: A convenience sample of highly selected ICH patients underwent frameless stereotactic aspiration and thrombolysis (FAST) of the clot. Two milligrams of rtPA were administered every 12 h until ICH volume < or =10 cc, or catheter fenestrations were no longer in continuity with the clot. ICH and perihematomal edema volumes were calculated from CT scans. Using random effects linear regression we estimated the rate of hematoma and edema volume resolution as well as their relationship during the first 8 days of lytic therapy. RESULTS: Fifteen patients were treated, mean age: 60.7 years, median time from ictus to FAST: 1 (range 0-3) day. Using a random effects model that considered volume resolution over the first 8 days following lytic therapy we found that the both percentage hematoma and percentage perihematoma edema resolution per day were quadratic with respect to time. Percentage residual hematoma volume on day K = 97.7% - [24.36%*K] + [1.89%*K (2)]; P < 0.001 for both terms. Percentage residual edema on day K = 97.4% - [13.94%*K] + [1.30%*K (2)]; P < 0.001 for K and P = 0.01 for K (2). Examination of each patient's volume data suggests that there exists a strong direct relationship between perihematoma edema volume and same day hematoma volume. CONCLUSIONS: In this cohort of ICH patients treated using FAST, volumetric analysis of ICH and perihematomal edema seems to suggest that local use of rtPA does not exacerbate brain edema formation. Furthermore, there seems to be a strong association between reduction in ICH volume and reduction in edema volume, as would be expected following the concept of "hemotoxicity" postulated by some investigators.

Specific heat of superconducting Zn nanowires.

We present heat capacity measurements on crystalline Zn nanowires with diameters of 230 and 23 nm, bracketing the superconducting coherence length of 155 nm. Transport measurements on superconducting nanowires have found a crossover from three-dimensional to one-dimensional behavior as the wire diameter was reduced below the coherence length. In contrast, the normalized heat capacity peak of the 23 nm Zn nanowires is found to be nearly identical to that of 230 nm wires and bulk Zn, indicating their thermodynamic properties remain three dimensional.

Open stand-up MRI: a new instrument for positional neuroimaging.

We present a 40-year-old man referred with complaints of neck pain, left arm pain, headaches, paresthesias in the index and middle fingers, with numbness in the C7 nerve root distribution. Conventional recumbent magnetic resonance imaging (MRI) was read by the radiologist as a small protrusion at C5-C6 that did not correlate with his symptoms. The patient had exhausted his treatment options. He underwent MRI in a weight-bearing, upright position with extension that revealed a positional cervical disc protrusion on the left at C6-C7. The protrusion was causing a proximal left C6-C7 neural foraminal stenosis and impingement that correlated with his symptoms. With this information, we were able to offer a targeted epidural block. Imaging the spine in the weight-bearing position with extension or placing the spine in the position of pain may increase the diagnostic accuracy for the neuroradiologist and neuroimagist, who then can provide the spine surgeon or neurosurgeon potentially with additional information to further improve patient care.

Frameless stereotactic aspiration and thrombolysis of spontaneous intracerebral hemorrhage.

INTRODUCTION: To test the feasibility and safety of a minimally invasive technique, we report our experience in treating spontaneous intracerebral hemorrhage (ICH) patients by using frameless stereotactic clot aspiration-thrombolysis and its effects on their 30-day survival. We compared the observed cohort mortality with its predicted 30-day ICH mortality, by using previously validated methods. METHODS: Selection criteria were diagnosis of hypertensive ICH > or =35 cc, reduced level of consciousness, and no brainstem compression. Frameless stereotactic puncture/clot aspiration followed by intraclot external catheter placement was performed. Two milligrams of recombinant tissue plasminogen activator (rtPA) was administered q12 hours until ICH volume < or =10 cc, or the catheter fenestrations were no longer in continuity with the clot. RESULTS: Fifteen patients were treated, mean age was 60.7 years. Hemorrhage locations included basal ganglia (13), thalamic (1), and lobar (1); mean systolic blood pressure; and admission ICH volumes were 229.3 mmHg and 59.1 cc, respectively. Median time from ictus to clot aspiration/thrombolysis was 1 (range 0-3) day. Mean hematoma volume was reduced to 17% of pretreatment size. Complications were ventriculitis (6.6%) and clot enlargement (13.3%). Two patients were dead at 30 days. Median Glasgow Coma Scale (GCS) scores were 10.5 (4-15) at admission and 11.0 (3-15) at discharge. By using the most conservative estimate for analysis, probability of observing two or fewer deaths among 15 patients with an overall probability of dying calculated at 0.33 was p = 0.079. CONCLUSIONS: In this selected cohort of patients with ICH, stereotactic aspiration and thrombolytic washout seemed to be feasible and to have a trend towards improved 30-day survival, when using their predicted mortality data as "historical control." Complications did not exceed expected incidence rates. Based on the experience presented here as well as previous similar reports, a larger, randomized study addressing dose escalation, patient selection, and best therapeutic window is needed.