Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.     

Defining Dry Eye from a Clinical Perspective

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: “Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.” The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.     

Inhalation toxicity of 1,6-hexanediamine dihydrochloride in F344/N rats and B6C3F1 mice

1,6-Hexanediamine (HDA) is a high production volume chemical which is used as an intermediate in the synthesis of paints, resins, inks, and textiles and as a corrosion inhibitor in lubricants. Two- and 13-week studies of the toxicity of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice using whole-body inhalation exposure. Both species were evaluated for histopathologic and reproductive effects, and rats were examined for clinical chemistry and hematologic changes. In the 2-week inhalation studies, animals were exposed to 10-800 mg HDDC/m3, 6 hr per day. All rats, all female mice, and two of five male mice in the high-exposure group died before the end of the study. Surviving mice in this group had a dose-dependent depression in body weight gain. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in both species. Treatment-related histopathologic lesions included inflammation and necrosis of the laryngeal epithelium of both species and the tracheal epithelium of mice, as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In the 13-week inhalation studies, animals were exposed to HDDC at concentrations of 1.6-160 mg/m3 for 6 hr per day, 5 days per week. In addition to the base study groups, a supplemental group of rats at each exposure level was included to assess the effect of HDDC on reproduction. No treatment-related changes in organ weights or organ-to-body-weight ratios occurred in rats, and no treatment-related clinical signs or gross lesions were seen in either species. Chemical-related microscopic lesions were limited to the upper respiratory tract (larynx and nasal passages) in the two highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion, ulceration, inflammation, and hyperplasia of the laryngeal epithelium, in addition to degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or vaginal cytology and no significant adverse effects on reproduction in rats or mice. Hematologic and clinical chemistry changes in rats were minor and sporadic and were not accompanied by related histologic findings. HDDC did not increase the frequency of micronucleated erythrocytes in mice.(ABSTRACT TRUNCATED AT 400 WORDS)     

An LP-based heuristic procedure for the generalized assignment problem with special ordered sets

The generalized assignment problem with special ordered sets (GAPS2), is the problem of allocating n tasks to m time-periods, where each task must be assigned to a time-period, or shared between two consecutive time-periods. For reasonably large values of m and n the NP-hard combinatorial problem GAPS2 becomes intractable for standard mathematical programming software, hence there is a need for heuristic algorithms to solve such problems. It will be shown how an LP-based heuristic developed previously for the well-established generalized assignment problem can be modified and extended to solve GAPS2. Encouraging results, in terms of speed and accuracy, in particular when compared to an existing heuristic for GAPS2, are described.     

Sub-100 fs Kerr lens modelocked Cr4+:YAG laser

Sub-100 fs pulse generation from a Kerr lens modelocked Cr⁴⁺ :YAG laser has been demonstrated for the first time, yielding femtosecond pulses tunable from 1.49 to 1.56 μm with pulses as short as 90 fs obtained at 1.53 μm     

2.488 Gb/s-318 km repeaterless transmission using erbium-dopedfiber amplifiers in a direct-detection system

The authors have achieved a 2.488 Gb/s, 318 km repeaterless transmission without any fiber dispersion penalty through a nondispersion-shifted fiber in a direct detection system. The system was loss limited with a T-R power budget of 57 dB. Three key components enabled the authors to achieve this result: (1) a Ti:LiNbO₃ external amplitude modulator enabling a dispersion-free transmission, (2) erbium-doped fiber amplifiers increasing the transmitting power to +16 dBm, and (3) an erbium-doped fiber preamplifier enabling a high-receiver sensitivity of -4.1 dBm for 10^-9 BER. To the author's knowledge, this result is the longest repeaterless transmission span length ever reported for direct detection at this bit rate. From the experimental results and a theoretical model, the authors identified the sources of the receiver sensitivity degradation from the quantum limit (-48.6 dBm) and estimated the practically achievable receiver sensitivity of ~-44 dBm (~-124 photons/bit) for 2.5 Gb/s optical preamplifier detection     

Analysis of an antijam FH acquisition scheme

An easily implemented matched filter scheme for acquiring hopping code synchronization of incoming frequency-hopping (FH) signals is analyzed, and its performance is evaluated for two types of jamming: partial-band noise jamming and partial-band multitone jamming. The system is designed to reduce jammer-induced false alarms. The system's matched filter output is compared to an adaptive threshold that is derived from a measurement of the number of acquisition channels being jammed. Example performance calculations are given for the frequency coverage of the jamming either fixed over the entire acquisition period or hopped, that is, changed for each acquisition pulse. It is shown that the jammer's optimum strategy (the worst case) is to maximize the false alarm probability without regard for the effect on detection probability, for both partial-band noise and multitone jamming. It is also shown that a significantly lower probability of false acquisition results from using an adaptive matched filter threshold, demonstrating that the strategy studied here is superior to conventional nonadaptive threshold schemes     

Towards a Dual-Tip STM Application in Mesoscopic Electron Transport

A new design for a dual-tip scanning tunneling microscope (STM) is presented. The design is a variation on the mechanically controllable break-junction with two electron beam-induced deposition nano-tips. The new design enables one to scan surfaces simultaneously with two probes having a nano-gap separation. By collecting the lateral current flowing between the tips, the transconductance map can then be compared with the STM images for local characterizations of the electron transport. Since the lateral beam carries the property of the density of states of the surface at momentum space, the dispersion of the electronic structure should give an orientation and position dependence of the local transconductance current. In addition, the reduced terminal separation, on the order of the characteristic mesoscopic length scales, is likely to be sensitive to a variety of typically observed interactions and interference effects.     

The effect of the scale of horizontal subsurface flow constructed wetlands on flow and transport parameters.

Horizontal subsurface flow constructed wetlands have proven their efficiency in treating wastewater and removing the pollutants of concern. Treatment efficiency depends on the wastewater residence time, which is a function of the hydraulic loading and the physical conditions of the constructed filter system, which can be described with effective parameters such as: hydraulic conductivity, porosity, dispersivity etc. Because spatial variability is often scale dependent, these effective parameters may be affected by the scale of the system being studied. In this paper the results of tracer experiments in constructed filters using saturated horizontal flow at three scales (small and medium lab scales and full-scale system) using the same filter media is reported. Light-weight aggregate (filter media termed Filtralite-P) was used at all scales. Increasing the scale was associated with increasing dispersivity, meanwhile hydraulic conductivity experienced dramatic reduction and variation by increasing the examined scale. Observed changes in the hydraulic parameters indicate that heterogeneity at different scales should be taken into account when the performance of LWA filters are evaluated from small-scale experiments.