Compact laser modulation system for a transportable atomic gravimeter.

Nowadays, atom-based quantum sensors are leaving the laboratory towards field applications requiring compact and robust laser systems. Here we describe the realization of a compact laser system for atomic gravimetry. Starting with a single diode laser operating at 780 nm and adding only one fiber electro-optical modulator, one acousto-optical modulator and one laser amplifier we produce laser beams at all the frequencies required for a Rb-87 atomic gravimeter. Furthermore, we demonstrate that an atomic fountain configuration can also be implemented with our laser system. The modulated system reported here represents a substantial advance in the simplification of the laser source for transportable atom-based quantum sensors that can be adapted to other sensors such as atomic clocks, accelerometers, gyroscopes or magnetometers with minor modifications.

Generation of combined half-integer Bessel-like beams using synthetic phase holograms.

We discuss the generation of combined half-integer Bessel-like (CHB) beams using synthetic phase holograms (SPHs). We assess the efficiency and accuracy of the SPHs, in the task of generating CHB beams. The proposal is illustrated by the implementation of CHB beams, which are experimentally generated in a setup based on a phase spatial light modulator. Also, we analyze, numerically and experimentally, the propagation of the generated CHB beams. As the main result, the SPHs are able to generate several CHB beams with relatively high accuracy. Additionally, it is obtained that the efficiency values of the SPHs are close to the theoretical predictions.

Modeling transport across the running-sandpile cellular automaton by means of fractional transport equations.

Fractional transport equations are used to build an effective model for transport across the running sandpile cellular automaton [Hwa et al., Phys. Rev. A 45, 7002 (1992)PLRAAN1050-294710.1103/PhysRevA.45.7002]. It is shown that both temporal and spatial fractional derivatives must be considered to properly reproduce the sandpile transport features, which are governed by self-organized criticality, at least over sufficiently long or large scales. In contrast to previous applications of fractional transport equations to other systems, the specifics of sand motion require in this case that the spatial fractional derivatives used for the running sandpile must be of the completely asymmetrical Riesz-Feller type. Appropriate values for the fractional exponents that define these derivatives in the case of the running sandpile are obtained numerically.

Characterization of a transition in the transport dynamics of a diffusive sandpile by means of recurrence quantification analysis.

Recurrence quantification analysis (RQA) is used to characterize a dynamical transition that takes place in the diffusive sandpile. The transition happens when a combination of the drive strength, diffusivity, and overturning size exceeds a critical value. Above the transition, the self-similar transport dynamics associated to the classical (nondiffusive) sandpile is replaced by new transport dynamics dominated by near system-size, quasiperiodic avalanche events. The deterministic content of transport dynamics, as quantified by RQA, turns out to be quite different in both phases. The time series analyzed with RQA in this work correspond to local sand fluxes at different radial locations across the diffusive sandpile.

EphB3 receptors function as dependence receptors to mediate oligodendrocyte cell death following contusive spinal cord injury.

We demonstrate that EphB3 receptors mediate oligodendrocyte (OL) cell death in the injured spinal cord through dependence receptor mechanism. OLs in the adult spinal cord express EphB3 as well as other members of the Eph receptor family. Spinal cord injury (SCI) is associated with tissue damage, cellular loss and disturbances in EphB3-ephrinB3 protein balance acutely (days) after the initial impact creating an environment for a dependence receptor-mediated cell death to occur. Genetic ablation of EphB3 promotes OL survival associated with increased expression of myelin basic protein and improved locomotor function in mice after SCI. Moreover, administration of its ephrinB3 ligand to the spinal cord after injury also promotes OL survival. Our in vivo findings are supported by in vitro studies showing that ephrinB3 administration promotes the survival of both oligodendroglial progenitor cells and mature OLs cultured under pro-apoptotic conditions. In conclusion, the present study demonstrates a novel dependence receptor role of EphB3 in OL cell death after SCI, and supports further development of ephrinB3-based therapies to promote recovery.

Cox-2 inhibition enhances the activity of sunitinib in human renal cell carcinoma xenografts.

BACKGROUND: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. METHODS: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. RESULTS: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. CONCLUSION: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC.

The benefits of digital thoracic drainage system for outpatients undergoing pulmonary resection surgery.

Since digital thoracic drainage system (DTDS) came onto the market, a number of its advantages have become clear, for example that of eliminating the differences between observers. The withdrawal of thoracic drainage has been found to be comfortable, safe and well tolerated by patients; it helps to reduce or eliminate the cost of hospital stay, because, according to the different series published in recent months, it is possible to withdraw drainage sooner and thus discharge patients earlier. Prospective studies are underway, but as yet nothing has been written about the possible benefits in outpatient surgery programmes. In this report we present our findings of 3 cases of patients undergoing pulmonary resection who were treated with continuous intra-domiciliary DTDS. Pending the results of a prospective study now underway our observation is that with properly selected patients this is a safe method.

Intravascular epithelioid hemangioendothelioma.

An epithelioid hemangioendothelioma arising from the right common femoral vein in a 50-year-old woman was treated by wide local excision and venous reconstruction with the ePTFE graft. This clinicopathologic entity is a rare cause of intravascular mass and is characterized by an intermediate malignant potential. To our knowledge, very few cases have been reported in the literature, and they are listed in this report. Gross and microscopic distinguishing features of epithelioid hemangioendothelioma are reviewed. Finally, clinical behavior is discussed and treatment options are suggested.

Pooled analysis of phosphatidylinositol 3-kinase pathway variants and risk of prostate cancer.

The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade >or=8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling.

Characterization of nondiffusive transport in plasma turbulence via a novel Lagrangian method.

A novel method to probe and characterize the nature of the transport of passive scalars carried out by a turbulent flow is introduced. It requires the determination of two exponents which encapsulate the statistical and correlation properties of the component of interest of the Lagrangian velocities of the flow. Numerical simulations of a magnetically confined, near-critical turbulent plasma, known to exhibit superdiffusive radial transport, are used to illustrate the method. It is shown that the method can easily detect the change in the dynamics of the radial transport that takes place after adding to the simulations a (subdominant) diffusive channel of tunable strength.

Derrame pericárdico, pericarditis y sepsis como complicación tardía de corrección de un pectus excavatum por técnica de Nuss / Pericardial effusion, pericarditis and sepsis as late complication of correction of a pectus excavatum with the Nuss technique

No disponible

Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells without inhibiting the Raf/MEK/ERK signaling cascade.

The antibiotic radicicol suppresses transformation in a variety of transformed cells. The antineoplastic effects of the drug have been attributed to the degradation of Raf and the inactivation of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreading, suppresses anchorage-independent cell growth, and increases the expression of the high-molecular weight tropomyosin isoform TM-2 in cells stably expressing a constitutively active form of MEK-1 as well as in ras-transformed cells. Furthermore, the reverting effects of the drug are achieved at concentrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90(RSK). In contrast, low concentrations of radicicol significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription. The lack of correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletion or disruption of proximal signaling events in the mitogen-activated protein kinase pathway are not the predominant mechanisms by which the drug suppresses the transformed phenotype. Our observation that low concentrations of radicicol block transcriptional activities mediated by AP-1 and SRF suggests that interference with signaling upstream of these transcription factors may contribute to the reverting effects of the drug.

Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis.

Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.

Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two phase II cytokine working group trials.

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m(2)/d intravenously (IV) and cisplatin 25 mg/m(2)/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m(2) subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m(2), and in group 2, SC IL-2 was given at 5.0 mU/m(2). RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.

A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma.

CNI-1493, an inhibitor of proinflammatory cytokines, was studied in a Phase I trial in melanoma and renal cancer patients receiving high-dose interleukin 2 (IL-2). Objectives of the study were to define the maximum tolerated dose (MTD) and toxicity of CNI-1493, to assess its pharmacological effects, and to define its pharmacokinetics. Twenty-four patients were treated in sequential cohorts with CNI-1493 doses from 2 through 32 mg/m2 daily. Patients first received only CNI-1493 daily for 5 days. After a 9-day rest, patients received two 5-day courses of IL-2 of 600,000 IU/kg every 8 h for up to 14 doses/course plus daily CNI-1493; courses were separated by a 9-day rest period. CNI-1493 administered alone was well tolerated at doses through 32 mg/m2; MTD was not reached. The only clinical toxicity attributed to CNI-1493 was occasional injection-site phlebitis. Grade 1 creatinine increases occurred in 1 of 7 patients at 4 mg/m2, in 1 of 1 patients at 25 mg/m2, and in 3 of 6 patients at 32 mg/m2 CNI-1493 alone. In combination with high-dose IL-2, CNI-1493 at > or = 25 mg/m2 seemed to exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m2, as compared with 1 of 16 patients at doses < or = 16 mg/m2. The MTD for CNI-1493 given with high-dose IL-2 was 16 mg/m2. The dose-limiting toxicity of IL-2 was hypotension in 63% of patients; overall tolerance to IL-2 was not improved by CNI-1493. However, relative to changes seen in a reference group receiving high-dose IL-2 alone, at doses > or = 4 mg/m2 CNI-1493 did show evidence of pharmacological activity as an inhibitor of tumor necrosis factor production.

Agranulocytosis and hemolytic anemia in patients with renal cell cancer treated with interleukin-12.

Interleukin-12 (IL-12) is a cytokine with effects on immune function and hematopoiesis. In this article, the authors describe two patients with renal cell cancer in whom grade 4 neutropenia and grade 3 hemolytic anemia developed, respectively, during treatment with twice-weekly intravenous recombinant human interleukin-12 (rhIL-12) during a phase 1 trial. The severe neutropenia was associated with bone marrow agranulocytosis and a preponderance of large granular lymphocytes in the peripheral blood, whereas the hemolytic anemia was negative for the Coombs test and associated with splenomegaly. The agranulocytosis and hemolytic anemia persisted after the rhIL-12 was stopped, but both subsequently responded to treatment with cyclophosphamide. steroids, or both. These findings indicate that rhIL-12 can induce unique hematologic toxic effects that can be reversed with immunosuppressive drugs.

Phosphatidylinositol 3-kinase/Akt activity regulates c-FLIP expression in tumor cells.

The caspase-8 homologue FLICE-inhibitory protein (FLIP) functions as a caspase-8 dominant negative, blocking apoptosis induced by the oligomerization of the adapter protein FADD/MORT-1. FLIP expression correlates with resistance to apoptosis induced by various members of the tumor necrosis factor family such as TRAIL. Furthermore, forced expression of FLIP renders cells resistant to Fas-mediated apoptosis. Although FLIP expression is regulated primarily by MEK1 activity in activated T cells, the oncogenic signaling pathways that regulate FLIP expression in tumor cells are largely unknown. In this report, we examined the roles of the MAP kinase and phosphatidylinositol (PI) 3-kinase signaling pathways in the regulation of FLIP expression in tumor cells. We observed that the MEK1 inhibitor PD98059 reduced FLIP levels in only 2 of 11 tumor cell lines tested. In contrast, disruption of the PI 3-kinase pathway with the specific inhibitor LY294002 reduced Akt (protein kinase B) phosphorylation and the levels of FLIP protein and mRNA in all cell lines evaluated. The introduction of a dominant negative Akt adenoviral construct also consistently reduced FLIP expression as well as the phosphorylation of the Akt target glycogen synthase kinase-3. In addition, infection of the same cell lines with a constitutively active Akt adenovirus increased FLIP expression and the phosphorylation of GSK-3. These data add FLIP to the growing list of apoptosis inhibitors in which expression or function is regulated by the PI 3-kinase-Akt pathway.

Kidney cancer: the Cytokine Working Group experience (1986-2001): part I. IL-2-based clinical trials.

The Cytokine Working Group (CWG) was initially established in 1986 as the Extramural IL-2/LAK Working Group. With funding from the National Cancer Institute (NCI), the CWG was mandated to confirming data regarding the efficacy of the high-dose interleukin-2 (IL2)/lymphokine-activated killer cell (LAK cell) regimen piloted at the NCI in the treatment of renal cell cancer. Since those initial studies, the CWG has conducted a series of clinical trials, often with correlative immunologic investigations, to evaluate combination immunotherapy in attempts to enhance the efficacy of IL-2 or to reduce toxicity. Subsequently, the CWG conducted trials to demonstrate the activity of lower-dose outpatient combination cytokine regimens to help determine their role in the armamentarium of treatment for metastatic renal cell cancer. This has culminated in a phase III randomized trial comparing the activity of high-dose IL-2 with the activity of outpatient IL-2 plus interferon-alpha. The CWG also has honed the management of both high-dose IL-2 and outpatient IL-2 regimens to make these safer in the hands of experienced clinicians. In addition, the CWG has produced a series of carefully conducted clinical trials of new cytokines, again attempting to define their clinical efficacy as anticancer agents. These include studies of IL-4, IL-6, and IL-12. Currently, the CWG is conducting studies with new approaches to IL-2 therapy, as well as planning trials with new agents for treatment of renal cell cancer. This review describes these efforts conducted over the past 15 yr.