Enhanced Computational Study with Experimental Correlation on I-V Characteristics of Tantalum Oxide (TaOx) Memristor Devices in a 1T1R Configuration.

Memristors, non-volatile switching memory platform, has recently attracted significant interest, offering unique potential to enable the realization of human brain-like neuromorphic computing efficiency. Memristors also demonstrate excellent temperature tolerance, long-term durability, and high tunability with nanosecond pulses, making them highly attractive for neuromorphic computing applications. To better understand the material processing, microstructure, and property relationship of switching mechanisms in memristor devices, computational methodologies, and tools are developed to predict the I-V characteristics of memristor devices based on tantalum oxide (TaOx) resistive random-access memory (ReRAM) integrated with an n-channel metal-oxide-semiconductor (NMOS) transistor. A multiphysics model based on coupled partial differential equations for electrical and thermal transport phenomena is solved for the high- and low-resistance states during the formation, growth, and destruction of a conducting filament through SET and RESET stages. These stages effectively represent the migration of oxygen vacancies within an oxide exchange layer. A series of parametric studies and energy minimization calculations are conducted to determine probable ranges for key material and model parameters accounting for the experimental data. The computational model successfully predicted the measured I-V curves across various gate voltages applied to the NMOS transistor in the one transistor one resistance (1T1R) configuration.

Emerging therapies in systemic lupus erythematous: from clinical trial to the real life.

Systemic lupus erythematous (SLE) is a chronic autoimmune disease characterised by multisystem involvement and a relapsing remitting course. SLE is a highly heterogeneous condition, with wide variations in both the presentation and severity of disease and the biological markers identified. The use of biologics in SLE has lagged behind that of other rheumatological conditions such as rheumatoid arthritis, in part due to the diverse clinical manifestations of SLE, making it difficult to design appropriate trials for novel treatments. As such, broad immunosuppressive treatment regimens are still widely used in SLE. Nevertheless, in recent years, elucidation of some aspects of SLE pathogenesis have allowed the development of therapies targeted at molecular mediators of SLE. This review provides an update of biological available therapies and those currently under development.

Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts.

Epinephrine and norepinephrine are produced during psychological stress and can directly bind to cells to induce DNA damage. These effects may have more long-lasting consequences such as DNA mutations resulting in an increased potential for cellular transformation and/or tumor progression. This study examined the molecular effects of a chronic (24 h) in vitro exposure to these stress hormones on murine 3T3 cells. Long exposures (24 h) in dose-response experiments with norepinephrine or epinephrine induced significant increases in DNA damage in treated cells compared to that of untreated controls as measured by the alkaline comet assay. Pre-treatment with a blocking agent (the ß-adrenergic receptor antagonist propranolol) eliminated this increase in damage. In addition, both norepinephrine and epinephrine increased cellular transformation, as assessed by growth in soft agar, and 3T3 cells pre-treated with either norepinephrine or epinephrine induced a more rapid onset of tumors and more aggressive tumor growth in nude mice. In summary, incubation of 3T3 cells with catecholamines results in long-term DNA damage as measured by increased transformed phenotypes and tumor progression, indicating that they are important mediators of stress effects on genomic instability and vulnerability to tumor formation.

Pain relief in palliative care: a focus on interventional pain management.

Pharmacological treatment forms the foundation of the management of pain in patients with advanced cancer. Although the majority of patients in the realm of palliative care can be provided with acceptable pain relief using the three-step WHO cancer pain guidelines, a significant minority still have pain that is not adequately controlled by conventional pharmacological management. Development of pain management strategies using a multidisciplinary input with appropriate and timely use of interventional pain management techniques can provide satisfactory pain relief for these patients, helping to reduce distress in the patient and their relatives during this difficult period. This clinical review aims to discuss the commonly used interventional techniques in pain management in palliative care. As patients with advanced cancer are the major recipients of palliative care services, the main focus of this article remains on pain management in advanced cancer. The use of central neuraxial blockade, autonomic blockade and peripheral nerve blocks are summarized.

V-Y advancement flap as first-line treatment for all chronic anal fissures.

INTRODUCTION: It was suggested that anal advancement flap be used to treat patients with chronic anal fissures that have failed medical management and have a low-pressure sphincter complex. We wished to assess anal advancement flap as a treatment for all chronic anal fissures. METHODS: All patients with chronic anal fissures regardless of their previous management underwent V-Y advancement flap. Patient demographics, symptom duration, previous treatments, short-term postoperative outcome and long-term follow-up were recorded. RESULTS: Fifty-four consecutive patients, median age 39 years (22-66), underwent a V-Y advancement flap over a 7-year period; 34 were men. Duration of symptoms ranged from 2 to 36 months with a median of 8 months. Forty-two patients (78%) had failed a previous therapy: glyceryl trinitrate (GTN) (25), GTN and diltiazem (16) and lateral sphincterotomy (one). Wound dehiscence occurred in three patients of which only one required a surgical intervention. On follow-up at 6 months, all but one patient had a healed wound and was asymptomatic. CONCLUSIONS: We have shown excellent rates of healing of chronic anal fissures treated with a V-Y advancement flap regardless of sphincter pressures, previous treatment and symptom chronicity. These results show the technique can be applied to all chronic fissures with success and used as a primary therapy.

Prevention of mammary carcinogenesis in MMTV-neu mice by cruciferous vegetable constituent benzyl isothiocyanate.

Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables, inhibits growth of human breast cancer cells in culture. The present study provides in vivo evidence for efficacy of BITC for prevention of mammary cancer in MMTV-neu mice. Administration of BITC at 1 and 3 mmol/kg diet for 25 weeks markedly suppressed the incidence and/or burden of mammary hyperplasia and carcinoma in female MMTV-neu mice without causing weight loss or affecting neu protein level. For example, cumulative incidence of hyperplasia/carcinoma was significantly lower in mice fed BITC-supplemented diets compared with control mice (P = 0.01 by Fisher's test). The BITC-mediated prevention of mammary carcinogenesis correlated with suppression of cell proliferation and increased apoptosis. The average number of Ki-67-positive cells in the carcinoma lesions of 3 mmol BITC group was lower by approximately 21% (P < 0.05) compared with tumors from control mice. Apoptotic bodies in the mammary tumor were higher by about 2- to 2.5-fold in the 1 and 3 mmol BITC treatment groups (P < 0.05) compared with control group. The BITC administration also resulted in overexpression of E-cadherin and infiltration of CD3(+) T-cells in the tumor. Although BITC treatment increased cytotoxicity of natural killer (NK) cells in vitro, dietary feeding of BITC failed to augment NK cell lytic activity in an ex vivo assay. The present study demonstrating efficacy of BITC against mammary cancer in an animal model provides impetus to determine its activity in a clinical setting.

Magnetic resonance imaging-guided adoptive cellular immunotherapy of central nervous system tumors with a T1 contrast agent.

Dendritic cells (DCs) are the most effective antigen-presenting cells (APCs) and are used in a variety of immunotherapeutic approaches. Adoptive cellular immunotherapy (ACI) of cancer using DCs has attracted much interest due to their capacity to promote immunity in prophylactic and therapeutic protocols. As one approach, DCs are injected into patients or tumor-bearing animals, to trigger specific antitumor immunity. In that framework, several approaches to DC delivery have been reported, including direct intratumoral injection; this has yielded positive but variable results. The underlying reasons for this have not been fully determined, but major hypotheses include technical difficulties in delivering cells into tumors and tumor-mediated immunosuppression. Image-guided ACI offers the potential to establish that DCs are efficiently delivered to the tumor site, which might eliminate some of the variability. Therefore, we developed highly sensitive methods for monitoring the injection or trafficking of DCs into tumors using a clinically approved formulation of a gadolinium-based magnetic resonance imaging (MRI) contrast agent, Gd(III)-HP-DO3A (ProHance). We determined the labeling efficiency of DCs with this formulation; that labeling DCs with this agent did not inhibit expression of surface markers important for antigen presentation and activation of naive T cells; that their capacity to interact with natural killer (NK) cells was not reduced; and that their migration was not diminished. Further, we determined that ProHance-labeled DCs can be effectively imaged in vivo in established central nervous system tumors.

Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells.

The present study shows that oral gavage of 6 mumol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were approximately 23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also approximately 44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited approximately 50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P < 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity.

Gaining experience with military medical situational awareness and geographic information systems in a simulated influenza epidemic.

The purpose of medical situational awareness is to provide useful and actionable information for preparing and employing medical assets in support of a wide variety of operational missions around the world, and monitoring and protecting the health of the force in the face of rapidly changing health threats. Since 2005, the Medical Situational Awareness in the Theater Advanced Concept Technology Demonstration has exploited advances in information technology, geographic information systems, and open systems architecture to produce a functioning prototype of a medical situational enhancement capability. In May 2006, this prototype supported the medical staff of a combined/joint task force in a realistic command postexercise featuring a simulated outbreak of influenza during Exercise COBRA GOLD in Thailand. The proliferation and maturation of geographic information systems present many opportunities for the military medical community to improve the health of the populations for which it is responsible.

Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones.

Stress is associated with increased production of sympathetic and other adrenal hormones. Epinephrine (E), norepinephrine (NE) and cortisol are produced during psychological stress and may affect many cells directly. These effects may be transient (e.g. heart rate, immune cell trafficking) or they can have more long-lasting consequences, such as permanent DNA damage which may result in increased cell transformation and/or tumorigenicity. Here, the molecular effects of short term in vitro exposure of these stress hormones were analyzed on murine 3T3 cells by measuring effects on DNA damage and repair, cell transformation and changes in mRNA expression of genes specifically involved in DNA damage signaling pathways. Short-term exposure (<30 min) to physiological concentrations of either cortisol, NE or E induced at least five-fold increases in DNA damage in treated cells compared to untreated controls. Pre-treatment with blocking agents such as the glucocorticoid receptor antagonist RU486, or the beta-adrenergic receptor antagonist propranolol, eliminated this increase in damage. Both cortisol and NE interfered with repair of DNA damage in cells exposed to UV and resulted in an increase in the transformed phenotype. In contrast, E had none of these effects on 3T3 cells. Stress hormones had no significant effects on cell cycle regulation. Targeted gene arrays showed that cortisol, NE and E modulated the transcription of 21, 14 and 18 genes, respectively. These genes were directly related to DNA damage signaling pathways, and included up-regulation of DNA damage sensors Chk1 and Chk2, and the proto-oncogene CDC25A, which is involved in cell cycle delay following DNA damage. Taken together, these data show that stress hormones can increase DNA damage and transformation and alter transcriptional regulation of the cell cycle.

CD161B:ClrB interactions mediate activation of enhanced lysis of tumor target cells following NK cell:DC co-culture.

Co-culture of natural killer (NK) cells and dendritic cells (DCs) results in their reciprocal co-activation, and an enhancement of lysis of tumor target cells. The receptor:ligand pairings mediating this enhancement are unknown. Therefore, we investigated whether interactions of CD161, on NK cells, with Clrs, on DCs, might have a role in this effect. Blocking expression of CD161B using siRNA resulted in a reduction in enhanced lytic activity following NK:DC co-culture. Conversely, blocking expression of CD161F with siRNA had no effect on enhanced lytic function following NK:DC co-culture. Blocking expression of ClrB/Ocil, a ligand for CD161B, resulted in a reduced level of enhanced lytic function following NK:DC co-culture. This is the first report of NK receptors responsible for interaction with DCs having a role in mediating enhanced lytic function following NK:DC interactions.

CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability.

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53(+/-) mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CIN-) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G > T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5' half of the gene. The reasons for this odd mutation spectrum were unclear but C:G > T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers.

Genomic profiling of restraint stress-induced alterations in mouse T lymphocytes.

DNA damage-, DNA repair-, and apoptosis-related gene expression in CD3(+) T lymphocytes of BALB/c mice subjected to 2-h restraint stress were compared to that in CD3(+)T lymphocytes from control mice. Using targeted cDNA arrays, significant increases in expression of genes serving as sensors of DNA damage, including MSH genes and RAD53, were observed. GADD45g, a gene responsible for regulating cell cycle arrest and apoptosis, was significantly induced; as was Pura, a gene involved in cell proliferation. These data suggest that, at the molecular level, stress activates genes responsible for priming the T cell to either undergo apoptosis or proliferation.

The characterization of tumor apoptosis after experimental radiosurgery.

We sought to evaluate whether radiosurgery induces apoptosis in an experimental glioma model and to elucidate the time course of this radiobiologic phenomenon. Fischer 344 rats harboring established intracranial 9L gliosarcomas underwent radiosurgery (n = 42) or no radiosurgery (n = 45). Animals were sacrificed at 3, 6, 12, 24, 48, 72 h, and 1 or 2 weeks after treatment and in situ tumor apoptosis was assessed by specific staining. Tumor apoptosis was noted to be statistically higher in radiosurgery-treated animals relative to controls at the 6-, 24-, and 48-hour time points following radiosurgery. Radiosurgery induces apoptosis in the rat intracranial 9L gliosarcoma in a time-dependent fashion. The time course of this radiobiologic phenomenon begins at approximately 6 h following radiosurgery, continues up to 48 h, and begins to decline by 72 h.

A collaborative approach to the development of psychiatric rehabilitation services in a public behavioral health managed care environment.

This article summarizes the collaborative effort that took place between providers, managed care administrators, and state and county officials in Pennsylvania to create a fluid system in the development of psychiatric rehabilitation services. The stakeholders involved solved the numerous logistical problems that are inherent in the start-up of new services and were able to cooperatively create procedures for service delivery, service coordination, and reimbursement across systems and funding mechanisms. The article reviews that process and highlights the services of Welcome House, a psychiatric rehabilitation program exemplifying the products of their collaboration.

A novel epitope of N-CAM defines precursors of human adherent NK cells.

Activated, adherent natural killer (A-NK) cells represent a distinct subpopulation of interleukin (IL)-2-stimulated NK cells, which are selectively endowed with the increased expression of integrins and ability to adhere to solid surfaces, migrate into, infiltrate, and destroy cancerous tissues. The present study defines the phenotype and functions of precursors of A-NK (pre-A-NK) cells in humans. Peripheral blood pre-A-NK cells, in contrast to the rest of NK cells, express a novel epitope of CD56 neuronal cell adhesion molecule, termed ANK-1, and increased cell-surface levels of integrins. Pre-A-NK cells also express low levels of CD56 and CD161, and some express CD162 receptor, do not express CD25 or activation markers, and are effective mediators of NK cytotoxicity. Thus, pre-A-NK cells are generally similar to CD56(dim) NK cells. However, pre-A-NK cells differ from the main NK cell subpopulation by having a lower expression level of CD16 and a lower ability to mediate redirected antibody-dependent, cell-mediated cytotoxicity. More importantly, pre-A-NK cells are preferentially endowed with the ability to rapidly respond to IL-2 by integrin-mediated adherence to endothelial cells, extracellular matrix, and plastic. This early, specific response of pre-A-NK cells to IL-2 is followed by their activation, vigorous proliferation, and differentiation into phenotypically and functionally similar A-NK cells. Pre-A-NK cells represent only approximately 26% of peripheral blood NK cells but encompass the majority of NK cells in normal and cancerous, solid tissues. We conclude that pre-A-NK cells represent a distinct subset of resting, mature NK cells with the characteristics indicative of their ability to migrate and reside in solid tissues.

Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines.

We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-alpha-transfected dendritic cells (DC-IFN-alpha) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c. challenge with ovalbumin-expressing M05 melanoma (class I+ and class II-negative). Notably, antiovalbumin CTL responses were observed in animals vaccinated with an ovalbumin-derived T helper epitope but only after the mice were challenged with M05 cells. This cross-priming of CTL was dependent on both CD4+ and CD8+ T cells. Because we observed that s.c., but not intracranial, tumors were infiltrated with CD11c+ DCs, and because IFN-alpha promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN-alpha-engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN-alpha prolonged survival. This was most notable for animals prevaccinated with both the CTL and T helper ovalbumin epitopes, with 60% (6 of 10) of mice (versus 0 of 10 of control animals) surviving for > 80 days after tumor challenge. DC-IFN-alpha appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN-alpha-treated mice exhibited enhanced levels of ovalbumin-specific CTL in draining cervical lymph nodes. On the basis of these results, we believe that local expression of IFN-alpha by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.

Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo.

Immunotherapy of gliomas has been forwarded as an attractive alternative to standard therapeutic modalities. Numerous observations indicate some therapeutic efficacy with this approach, but it is not curative in most reports. It is well established that gliomas suppress immune reactivity via a number of mechanisms, including expression CD95 ligand (CD95L), which induces apoptosis of immune effector cells, and secretion of immunosuppressive factors such as transforming growth factor-beta (TGFbeta). It has been hypothesized that abrogation of production or function of TGFbeta would improve immune reactivity to gliomas. To investigate this in a fashion that is translatable into clinical practice, we utilized a retroviral vector encoding a truncated, soluble form of the Type II receptor for TGFbeta (TFGbeta sr) and expressed it in the rat 9L gliosarcoma line (9L-TGFbeta sr). We then determined whether expression of TGFbeta sr affected in vitro sensitivity of 9L to lysis by immune effector cells, whether expression of TGFbeta sr affected tumorigenesis of 9L in vivo, and whether TGFbeta sr affected expression of immunity to 9L. In these experiments, we determined that 9L-TGFbeta sr was more susceptible than sham transfected 9L (9L-neo) to lysis by natural killer (NK) cells. We also determined that subcutaneously implanted 9L-TGFbeta sr was less tumorigenic than 9L-neo in syngeneic rats. Similarly, survival was extended by approximately 40% in rats given intracranial 9L-TGFbeta sr compared to 9L-neo. Finally, we determined that elimination of CD161+ cells resulted in comparable growth of 9L-neo and 9L-TGFbeta sr in vivo, indicating that NK or NK-like cells were responsible for the anti-tumor effects in this model.

Stability of individual differences in cellular immune responses to two different laboratory tasks.

To explore the stability of immune reactivity across laboratory tasks, we correlated enumerative and functional lymphocyte responses to a speech task and a mental arithmetic task, delivered on the same occasion of testing in 31 healthy undergraduates. Both tasks were associated with an increase in peripheral CD8+ and CD56+ cell populations, and a decrease in proliferative response to phytohemagglutinin (PHA) and ratio of CD4:CD8 cells. Intertask correlations were significant for the magnitude of change in proliferative responses at two different concentrations of PHA, r = 0.76, p < .0001 and r = 0.46, p < .05, and in numbers of circulating CD56+ cells, r = 0.46, p < .005. Concomitant heart rate and systolic blood pressure responses also correlated significantly over the two experimental tasks (heart rate: r = 0.52 and systolic blood pressure: r = 0.58. ps < .0005). These data provide initial evidence that interindividual variability of some cellular immune responses is moderately reproducible across different stimulus conditions, providing further evidence that it may denote a stable individual difference.