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BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (pConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Purpose To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). Methods Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. Results Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). Conclusion Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.

The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5μg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p=0.009), and 88% by MH (p=0.004; PGFM vs. MH: p=0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5μg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 hour of reconstitution) vs. four hours after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, which were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical difference between formulations. Comparing those patient eyes treated exclusively with PGFM versus those treated exclusively with MH, efficacy for tumor control and globe salvage was equivalent (PGFM vs. MH: 96.2% vs. 93.8%, p=0.56), but PGFM-treated eyes received fewer injections than MH-treated eyes (average 3.2±1.9 vs. 6.4±2.1 injections, p

The broadband photothermoelectric effect has been studied on a graphene-2D semiconductor lateral heterojunction., The massless Dirac electron transport in graphene has led to a variety of unique light-matter interaction phenomena, which promise many novel optoelectronic applications. Most of the effects are only accessible by breaking the spatial symmetry, through introducing edges, p-n junctions, or heterogeneous interfaces. The recent development of direct synthesis of lateral heterostructures offers new opportunities to achieve the desired asymmetry. As a proof of concept, we study the photothermoelectric effect in an asymmetric lateral heterojunction between the Dirac semimetallic monolayer graphene and the parabolic semiconducting monolayer MoS2. Very different hot-carrier cooling mechanisms on the graphene and the MoS2 sides allow us to resolve the asymmetric thermalization pathways of photoinduced hot carriers spatially with electrostatic gate tunability. We also demonstrate the potential of graphene-2D semiconductor lateral heterojunctions as broadband infrared photodetectors. The proposed structure shows an extreme in-plane asymmetry and provides a new platform to study light-matter interactions in low-dimensional systems.

Purpose To refine the Minnesota Grading System (MGS) using definitions from the Age-Related Eye Disease Studies (AREDS) into a nine-step grading scale (MGS-9). Methods A nine-step grading scale descriptive analysis using three key phenotypic features (total drusen area, increased, and decreased pigmentation) of human eyebank eyes that were graded according to definitions from the AREDS criteria in order to harmonize studies of disease progression for research involving human tissue. From 2005 through February 2017, we have analyzed 1159 human eyes, procured from two eyebanks. Each macula was imaged using high-resolution, stereoscopic color fundus photography with both direct- and transillumination. Fundus images were digitally overlaid with a grading template and triangulated for foveal centration. Results We documented and stratified risk for each globe by applying the AREDS nine-step grading scale to the key clinical features from the MGS-9. We found a good distribution within the MGS categories (1-9) with few level eight globes. Eyes were processed within 12.1 ± 6.3, hours from the time of death through imaging, dissection, and freezing or fixation. Applying the MGS-9 to 331 pairs (662 eyes were simultaneously graded), 84% were within one-grading step and 93% within two steps of the fellow eye. We also document reticular pseudodrusen, basal laminar drusen, and pattern dystrophy. Conclusions The MGS nine-step grading scale enables researchers using human tissue to refine the risk assessment of donor tissue. This analysis will harmonize results among researchers when grading human tissue using MGS criteria. Most importantly, the MGS-9 links directly to the known risk for progression from the AREDS.

Purpose The purpose of this study was to correlate magnetic resonance imaging (MRI) radiographic results with histopathologic growth patterns of metastatic uveal melanoma (UM) to the liver. Design Clinicopathologic correlation. Participants Patients with metastatic UM to the liver. Methods A retrospective review of MRI images of patients with metastatic UM to the liver at a single institution between 2004 and 2016 was performed. The MRI growth patterns were classified as nodular or diffuse. The histopathologic findings of core liver biopsies of liver metastases identified by needle localization in a subset of these patients were reviewed. The core samples were evaluated by routine light microscopy, including immunohistochemical/immunofluorescent staining for CD31, CD105, and HMB45, and classified as exhibiting an infiltrative or nodular growth pattern. Main Outcome Measures Magnetic resonance images and core biopsy findings. Results A total of 32 patients were identified with metastatic UM to the liver that was imaged by MRI, and 127 lesions were identified. A total of 46 lesions were classified by MRI as infiltrative and 81 as nodular. There were 9 needle-localized core biopsies that corresponded to MRI of metastatic lesions. Of these 9 lesions, 3 that were classified as infiltrative on MRI exhibited stage I infiltrative histologic growth patterns; of the remaining 6 that were classified as nodular by MRI, 5 histologically demonstrated stage II or stage III infiltrative growth patterns and 1 histologically demonstrated a nodular growth pattern. Conclusions Magnetic resonance imaging of hepatic infiltrative growth patterns of metastatic UM corresponded to stage I histologic infiltrative growth in the sinusoidal spaces, whereas MRI nodular growth patterns corresponded to stage II/III histologic infiltrative growth that replaced the hepatic lobule or histologic nodular growth in the portal triad that effaced adjacent hepatic parenchyma.

Background: Ballistic fractures of the carpus and hand are routinely treated in large urban centers. These injuries can be challenging due to many factors. Various treatment options exist for these complicated injuries, but there are limited data available. This report analyzes patient demographics, treatments, and outcomes at a large urban trauma center. Methods: All ballistic fractures of the hand and wrist of the patients who presented to a single center from 2011 to 2014 were retrospectively reviewed. Patient demographics, injury mechanism, treatment modalities, and outcomes were analyzed. Results: Seventy-seven patients were identified; 70 were male, and 7 were female. Average age of the patients was 29.6 years. Seventy-five injuries were low velocity, whereas 2 were high velocity. Sixty-seven patients had fractures of a metacarpal or phalanx, whereas 4 had isolated carpal injuries. Six had combined carpal and metacarpal or phalanx fractures. Thirty-six patients had concomitant tendon, nerve, or vascular injuries requiring repair. Sixty-three patients underwent operative intervention, with the most common intervention being percutaneous fixation. Sixteen patients required secondary surgery. Eighteen complications were reported. Conclusions: The majority of patients in this report underwent early operative intervention with percutaneous fixation. Antibiotics were administered in almost all cases and can usually be discontinued within 24 hours after surgery. It is important to consider concomitant nerve, vascular, or tendon injuries requiring repair. We recommend early treatment of these injuries with debridement and stabilization. Due to lack of follow-up and patient noncompliance, early definitive treatment with primary bone grafting should be considered.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy with a high propensity for regional lymph node metastasis and recurrence. Acute febrile neutrophilic dermatosis (Sweet syndrome) is an acute inflammatory skin eruption that is commonly associated with hematologic malignancies, but cases in association with solid tumors have also been reported. We present the first case of a 49-year-old female who experienced an acute flare up of Sweet syndrome during her initial diagnosis and subsequent treatment for MCC.

Proteasome inhibition is an approved cancer therapy. Quiescent fibroblasts are much more resistant to proteasome inhibition–induced death than proliferating fibroblasts. Mechanisms that protect quiescent fibroblasts include autophagy/lysosomal pathways, diminished aggresome formation, and detoxification of reactive oxygen species., Proteasome inhibition is used as a treatment strategy for multiple types of cancers. Although proteasome inhibition can induce apoptotic cell death in actively proliferating cells, it is less effective in quiescent cells. In this study, we used primary human fibroblasts as a model system to explore the link between the proliferative state of a cell and proteasome inhibition–mediated cell death. We found that proliferating and quiescent fibroblasts have strikingly different responses to MG132, a proteasome inhibitor; proliferating cells rapidly apoptosed, whereas quiescent cells maintained viability. Moreover, MG132 treatment of proliferating fibroblasts led to increased superoxide anion levels, juxtanuclear accumulation of ubiquitin- and p62/SQSTM1-positive protein aggregates, and apoptotic cell death, whereas MG132-treated quiescent cells displayed fewer juxtanuclear protein aggregates, less apoptosis, and higher levels of mitochondrial superoxide dismutase. In both cell states, reducing reactive oxygen species with N-acetylcysteine lessened protein aggregation and decreased apoptosis, suggesting that protein aggregation promotes apoptosis. In contrast, increasing cellular superoxide levels with 2-methoxyestradiol treatment or inhibition of autophagy/lysosomal pathways with bafilomycin A1 sensitized serum-starved quiescent cells to MG132-induced apoptosis. Thus, antioxidant defenses and the autophagy/lysosomal pathway protect serum-starved quiescent fibroblasts from proteasome inhibition–induced cytotoxicity.

The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

OBJECTIVES/SPECIFIC AIMS: Evidence-based guideline-concordant care leads to better outcomes in patients with early stage breast cancer, including survival. However, previous studies of guideline compliance have been limited by small study sample sizes, localized geography, unknown causal factors, and lack of diverse population. We use a national database to assess socio-economic, clinical, and facility factors that impact treatment compliance with evidence-based guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). METHODS/STUDY POPULATION: This is a retrospective cohort study of the National Cancer Data Base Participant User File Breast 2014, which captures ~70%–80% of all newly diagnosed cancer cases in the United States. Female patients who were diagnosed with early stage breast adenocarcinoma (T0, T1, T1A, T1B, 2, 2A, or T2N1) from 2004 to 2014 were eligible for this study. RESULTS/ANTICIPATED RESULTS: A total of 807,314 patients were included in this study. Evidence-based guidelines examined with associated compliance rates include surgery completion (79.3% overall compliance), breast conserving surgery Versus mastectomy (88.05% vs. 11.95%, respectively), radiation after breast conserving surgery (77.5% overall compliance), HER2 testing (88.6% overall compliance), estrogen/progesterone receptor (ER/PR) testing (96.3% overall compliance), hormone treatment for positive ER/PR breast cancer (80.2% overall compliance), and sentinel lymph node biopsy completion (67.5% overall compliance). Univariate association between these guidelines and covariates such as facility type, facility location, age, race, insurance status, median income quartiles, achievement of high school degree, urban Versus rural, Charlson-Deyo score, year of diagnosis, and overall survival were assessed. Logistic regression analysis will be used to determine multivariate relationships between these characteristics and the probability that a patient will be compliant to guideline regimen. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will help identify socio-economic, clinical, and facility factors that influence guideline-concordant care and subsequent critical outcomes for patients with early stage breast cancer. Lack of guideline concordant care for specific stages of cancer or treatment modalities will point to a need for tailored interventions to enhance compliance. A prediction model will help identify the most important predictors of noncompliance in breast cancer treatment so noncompliance can be prevented in at-risk populations.

Phase-change materials (PCMs) are promising candidates for nonvolatile data storage and reconfigurable electronics, but high programming currents have presented a challenge to realize low-power operation. We controlled PCM bits with single-wall and small-diameter multi-wall carbon nanotubes. This configuration achieves programming currents of 0.5 microampere (set) and 5 microamperes (reset), two orders of magnitude lower than present state-of-the-art devices. Pulsed measurements enable memory switching with very low energy consumption. Analysis of over 100 devices finds that the programming voltage and energy are highly scalable and could be below 1 volt and single femtojoules per bit, respectively.

The integration of carbon nanotubes with silicon is important for their incorporation into next-generation nano-electronics. Here we demonstrate a non-volatile switch that utilizes carbon nanotube networks to electrically contact a conductive nanocrystal silicon filament in silicon dioxide. We form this device by biasing a nanotube network until it physically breaks in vacuum, creating the conductive silicon filament connected across a small nano-gap. From Raman spectroscopy, we observe coalescence of nanotubes during breakdown, which stabilizes the system to form very small gaps in the network~15 nm. We report that carbon nanotubes themselves are involved in switching the device to a high resistive state. Calculations reveal that this switching event occurs at ~600 °C, the temperature associated with the oxidation of nanotubes. Therefore, we propose that, in switching to a resistive state, the nanotube oxidizes by extracting oxygen from the substrate.

We examine the effect of van der Waals (vdW) interactions between atomic force microscope tips and individual carbon nanotubes (CNTs) supported on SiO2. Molecular dynamics (MD) simulations reveal how CNTs deform during atomic force microscopy (AFM) measurement, irrespective of the AFM tip material. The apparent height of a single- (double-) walled CNT can be used to estimate its diameter up to ∼2 nm (∼3 nm), but for larger diameters the CNT cross-section is no longer circular. Our simulations were compared against CNT dimensions obtained from AFM measurements and resonant Raman spectroscopy, with good agreement for the smaller CNT diameters. In general, AFM measurements of large-diameter CNTs must be interpreted with care, but the reliability of the approach is improved if knowledge of the number of CNT walls is available, or if additional verification (e.g., by optical techniques) can be obtained. Open image in new window

We investigate high-field transport in graphene nanoribbons (GNRs) on SiO2, up to breakdown. The maximum current density is limited by self-heating, but can reach >3 mA/um for GNRs ~15 nm wide. Comparison with larger, micron-sized graphene devices reveals that narrow GNRs benefit from 3D heat spreading into the SiO2, which enables their higher current density. GNRs also benefit from lateral heat flow to the contacts in short devices (< ~0.3 um), which allows extraction of a median GNR thermal conductivity (TC), ~80 W/m/K at 20 C across our samples, dominated by phonons. The TC of GNRs is an order of magnitude lower than that of micron-sized graphene on SiO2, suggesting strong roles of edge and defect scattering, and the importance of thermal dissipation in small GNR devices., this version (v3) is very similar to that ultimately published in PRL

Phase-change materials (PCM) like Ge 2 Sb 2 Te 5 (GST) have been proposed for non-volatile memory and reconfigurable electronics [1, 2]. One of the drawbacks associated with this technology is the relatively high (∼0.5 mA) programming currents required [3]. In this work, we utilize carbon nanotubes (CNTs) as nano-scaled interconnects to induce reversible switching in very small GST bits (∼10 nm). This lowers the programming currents to

We describe a pulsed measurement technique for suppressing hysteresis for carbon nanotube (CNT) device measurements in air, vacuum, and over a wide temperature range (80-453 K). Varying the gate pulse width and duty cycle probes the relaxation times associated with charge trapping near the CNT, found to be up to the 0.1-10 s range. Longer off times between voltage pulses enable consistent, hysteresis-free measurements of CNT mobility. A tunneling front model for charge trapping and relaxation is also described, suggesting trap depths up to 4-8 nm for CNTs on SiO2. Pulsed measurements will also be applicable for other nanoscale devices such as graphene, nanowires, or molecular electronics, and could enable probing trap relaxation times in a variety of material system interfaces.

We study high-field electrical breakdown and heat dissipation from carbon nanotube (CNT) devices on ${\text{SiO}}_{2}$ substrates. The thermal ``footprint'' of a CNT caused by van der Waals interactions with the substrate is revealed through molecular dynamics simulations. Experiments and modeling find the CNT-substrate thermal coupling scales proportionally with CNT diameter and inversely with ${\text{SiO}}_{2}$ surface roughness $(\ensuremath{\sim}d/\ensuremath{\Delta})$. Comparison of diffuse mismatch modeling and data reveals the upper limit of thermal coupling $\ensuremath{\sim}0.4\text{ }\text{W}\text{ }{\text{K}}^{\ensuremath{-}1}\text{ }{\text{m}}^{\ensuremath{-}1}$ per unit CNT length at room temperature, ($130\text{ }\text{MW}\text{ }{\text{K}}^{\ensuremath{-}1}\text{ }{\text{m}}^{\ensuremath{-}2}$ per unit area), and $\ensuremath{\sim}0.7\text{ }\text{W}\text{ }{\text{K}}^{\ensuremath{-}1}\text{ }{\text{m}}^{\ensuremath{-}1}$ at $600\text{ }\ifmmode^\circ\else\textdegree\fi{}\text{C}$ for the largest diameter ($\ensuremath{\sim}$3.2 nm) CNTs. We also find semiconducting CNTs can break down prematurely and display more variability due to dynamic shifts in threshold voltage, which metallic CNTs are immune to; this poses a fundamental challenge for selective electrical breakdowns in CNT electronics.

Introduction The significance of 18-fluorodeoxyglucose PET/CT for predicting the estimation of a positive biopsy in cases of lymphoma is unknown. Diagnosis of lymphoma is based on a lymph node biopsy, however, the use of 18-fluorodeoxyglucose PET/CT for selecting a biopsy site that would provide the best the yield for accurate diagnosis remains unknown. Patients and Methods Data on 165 patients with initial suspicion of lymphoma that underwent PET/CT scans and biopsy as part of their initial evaluation were prospectively collected and reviewed. Standadized uptake value (SUVmax) of the biopsy site and others was collected from radiology reports. The association between the SUVmax on FDG-PET/CT before excision and the estimation of lymphoma diagnosis at biopsy was examined using a receiver operating characteristics curve analysis (ROC). Results 159/165 (84.5%) cases suspected of lymphoma underwent PET/CT scan performed prior excisional/FNA biopsy. Ninety six cases were diagnosed of diffuse large B cell lymphoma (DLBCL), 24 follicular lymphoma, 34 Hodgkin lymphoma, 15 plasmablastic lymphomas, and 6 marginal zone lymphoma. Receiver operating characteristics curve analysis demonstrated an area under the curve (AUC) of 0.6 with a borderline p-value of 0.06, which reached level of significance when the methodology of diagnosis only involved fine needle aspiration (FNA, AUC: 0.645, p= 0.05) or when the analysis was performed in patients with a diagnosis of follicular lymphoma (AUC:0.8, p Conclusion SUVmax on FDG-PET/CT is potentially useful for guiding biopsy sites that will provide the best yield to diagnose lymphoma. SUVmax is particularly useful to diagnose lymphoma when FNA is performed as diagnostic procedure of choice. We identified that tumor type, stage and LDH can affect SUV intensity. Performing a Receiver operating characteristics curve analysis of the SUVmax on FDG-PET/CT in a larger samples size is warranted for defining thresholds that predict the estimation of a positive biopsy. Disclosures Cohen: Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy; BMS, Janssen: Research Funding. Flowers:TG Therapeutics: Research Funding; Seattle Genetics: Consultancy; Acerta: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Genentech: Research Funding; Onyx Pharmaceuticals: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Infinity Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Celgene: Research Funding; OptumRx: Consultancy; Janssen: Research Funding. Bernal-Mizrachi:Takeda: Research Funding; Empire Genomics: Consultancy, Patents & Royalties.

Objectives: The aim of this study is to investigate quiescence-related resistance to proteasome-inhibition mediated proteotoxicity, and its regulatory mechanisms. Introduction: Quiescence, the reversible arrest of cellular proliferation, is critical for normal cellular development and tissue maintenance. Moreover, while proteasome inhibitors (PIs) are used to treat specific cancers, it has been shown that subsets of cells within a tumor, through quiescence, avoid PI-induced apoptosis and survive. Thus, deciphering the mechanisms through which quiescent cells resist proteasome inhibition is of basic and clinical relevance. Methods: Proliferating and quiescent primary human fibroblasts were used as a model system to study the effects of PIs (MG132, epoxomycin and Bortezomib). Flow cytometry, Western blots, microscopy and microarrays were used to identify specific pathways activated by proliferating and quiescent fibroblasts in response to proteasome inhibition. Results: We found that the proteasome-inhibited quiescent fibroblasts maintain viability while proliferating fibroblasts rapidly undergo apoptosis. We further found that proteasome-inhibited proliferating and quiescent fibroblasts up-regulate multiple protective pathways, including authophagy, chaperones and antioxidants, and evidence no observable difference in proteasome-mediated degradation pathway activity. However, we found that in proliferating fibroblasts, proteasome inhibition leads to increased reactive oxygen species (ROS), peri-nuclear protein aggresomes, and apoptotic cell death. By comparison, proteasome-inhibited quiescent cells display selective up-regulation of MnSOD (a ROS detoxifying enzyme), dispersed protein aggregates, and less apoptotic cell death. Knockdown of p62/SQSTM1 (a protein important for aggresome formation) or treatment with an antioxidant N-acetylcysteine results in reduced aggresome formation and decreased apoptosis in response to proteasome inhibition. Moreover, inhibition of autophagy sensitizes serum-starved quiescent cells to proteasome inhibition induced apoptosis. This suggests that multiple mechanisms, including autophagy, ROS detoxification and differential subcellular trafficking of ubiquitinated proteins are implicated in quiescence-related resistance to PI-induced apoptosis. These results point to possible strategies for improving the effectiveness of PIs in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2033. doi:1538-7445.AM2012-2033

Heat dissipation in electrically biased individual semiconducting carbon nanotubes (CNTs) on single crystal quartz and amorphous SiO2 is examined with temperature profiles obtained by spatially resolved Raman spectroscopy. Despite the differences in phonon velocities, thermal conductivity, and van der Waals interactions with CNTs, on average, heat dissipation into single crystal quartz and amorphous SiO2 is found to be similar. Large temperature gradients and local hot spots often observed underscore the complexity of CNT temperature profiles and may be accountable for the similarities observed.

not Available.

Carbon nanotube (CNT) heaters with sub-5 nm diameter induce highly localized phase change in Ge2Sb2Te5 (GST) chalcogenide. A significant reduction in resistance of test structures is measured as the GST near the CNT heater crystallizes. Effective GST heating occurs at currents as low as 25 uA, significantly lower than in conventional phase change memory with metal electrodes (0.1-0.5 mA). Atomic force microscopy reveals nucleation sites associated with phase change in GST around the CNT heater. Finite element simulations confirm electrical characteristics consistent with the experiments, and reveal the current and phase distribution in GST.

Abstract 3240 Poster Board III-177 Lymphomas are heterogeneous diseases comprising multiple clinical and biological subgroups. Several studies have shown that genomic instability and constitutive activation of the NF-kB pathway are key features for lymphoma development (Shen M,Hematologica 2007). However, it remains unclear whether changes in activation of the canonical and non-canonical NF-kB pathways (rel-A/p50 and rel-B/p52, respectively) reflect a response to genomic instability and therefore promotes lymphomagenesis. To answer this question, we first demonstrated in two lymphoma cell lines (Daudi and OCI-Ly3) that DNA damage induced by Doxorubicin (2 mcg/mL) resulted in nuclear localization of rel-A and Rel-B. Then, to determine the role of each NF-kB pathway in DNA repair and centrosome duplication we compared the number of cells positive for phospo-H2aX (pH2aX) and centrosomes numbers (measured by gamma-tubulin) in p105-siRNA (canonical) and P100-siRNA (non-canonical) with luciferase-siRNA (control) expressing cells. Our results showed that the expression of p105 and p100 siRNAs increase the number of pH2aX (+) cells compared to control. Subsequently, a time course measuring pH2aX (+) cells was performed after treating p105, P100 and luciferase siRNA OCI-ly3 expressing cell lines with Doxorubicin (2 mcg/mL). In cells expressing luciferase siRNA, pH2aX (+) cells peak (60%) at 60 minutes (min) and return to normal at 120 min, in p105 siRNA –cells pH2aX peak at 90 min (90% + cells) and then decrease similarly to luciferase siRNA cells. P100 siRNA cells demonstrate a continuous increased in pH2aX (+) cells up to 80%. In addition, p100 siRNA expression was associated with centrosome amplification (>2 centrosomes in 20-30% of the cells vs. < 8% in p105 or Luciferase siRNA expressing cells). Also, the expression of NF-kB siRNAs delayed doxorubicin-induced phosphorylation of p53 (serine 15 – target of ATM) and CHK2. To evaluate whether the genomic instability caused by both NF-kB siRNAs affects tumor development, we performed xenograft experiments. Our results demonstrated that NF-kB siRNAs not only slow down tumor initiation but prevented tumor development (p105 siRNA= 8 days delayed and 22% were tumor free and p100 siRNA= 13.5 days delayed and 55% were tumor free compared to luciferase siRNA). To investigate these findings in primary tissues we measured the number of phospo-H2aX (+) cells and the levels of rel-A and rel-B nuclear localization in 40 primary lymphoma tumor samples. Our results demonstrated that phospo-H2aX levels inversely correlated with rel-B nuclear localization (r=-0.58, p Disclosures No relevant conflicts of interest to declare.