Neurotropic malignant melanoma occurring in a stable burn scar

Malignant melanoma occurring in burn scars is extremely rare. Nine cases are reported in the literature. We report a case of a small malignant melanoma arising in a stable thermal burn scar after a long latent period of 58 years. The case was unique in that it was of the de novo neurotropic variant. Fascicles of amelanotic, S100 protein-positive atypical spindle cells with neuroid appearance infiltrated deeply in the scarred dermis and perineural spaces. The pigmentation of the lesion was due to solar lentigo instead of atypical melanocytic proliferation in the overlying epidermis.     

Role of afferent input of subcortical origin in the genesis of bilaterally synchronous epileptic discharges of feline generalized penicillin epilepsy.

The effects of (i) neural isolation of large bilateral cortical slabs with intact callosal connections, and (ii) of large unilateral subtotal thalamectomies associated with transection of the interhemispheric commissures on the generalized epileptiform discharges of generalized penicillin epilepsy of the cat were studied. Cortex devoid of subcortical, particularly thalamic, inputs was incapable of generating the characteristic 3.5- to 5-cycles/s epileptiform bursts of feline generalized penicillin epilepsy either in response to the i.m. injection of a large dose of penicillin or to the diffuse direct cortical application of a dilute penicillin solution. Such deafferented cortex, however, produced, even without penicillin, widespread often highly synchronized epileptiform discharges of a different kind consisting at times of slow, 1- to 2.5-cycles/s spike and wave complexes. This epileptiform activity increased in response to i.m. penicillin injection or to widespread direct cortical application of a dilute penicillin solution, but never assumed the characteristics of the typical discharges of feline generalized penicillin epilepsy as seen in cortex which has retained its subcortical connections. The discharges differed from those of intact cortex by being slower in frequency and less prone to become organized in bursts. In the bilateral slab preparation with preserved callosal connections, these atypical discharges occurred, however, in a bilaterally synchronous manner, as did the typical discharges in the intact cat with generalized penicillin epilepsy. This suggests that the corpus callosum is necessary for the bilateral synchrony of both types of epileptiform discharges.     

The pharmacokinetics and pharmacodynamics of fludarabine phosphate in patients with renal impairment: a prospective dose adjustment study

A significant number of chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma and Waldenstr?m's macroglobulinemia patients, treated with fludarabine phosphate (fludarabine), are elderly with diminished renal function. Since the kidney eliminates approximately 60% of fludarabine's primary metabolite (F-ara-A), dose modification is necessary for all patients with impaired renal function including elderly patients. In this study, 22 patients with varying levels of renal function received a single intravenous dose of fludarabine (25 mg/m3), followed one week later by five (one per day) doses that were adjusted according to three predefined creatinine clearance (CLcr) levels. Relationships between renal function and F-ara-A clearance, F-ara-A exposure and F-ara-A--related toxicities were examined. The results demonstrate that total F-ara-A clearance correlated with CLcr and that F-ara-A exposure levels and patient toxicity profiles were similar across treatment groups. IN CONCLUSION: The CLcr-based fludarabine dose adjustments used in this study provided reasonably equivalent F-ara-A exposure with acceptable safety in patients with varying degrees of renal function.     

Israeli oncology and nononcology nurses' attitudes toward physician-assisted dying: a comparison study

PURPOSE/OBJECTIVES: To compare the attitudes of Israeli oncology and nononcology nurses toward physician-assisted dying (PAD) and its legalization and to determine the factors that may be related to their attitudes. DESIGN: Nonrandomized, correlational study. SETTING: A teaching hospital in Jerusalem, Israel. SAMPLE: 71 oncology nurses and 52 nurses working in the maternity and nursery departments. RESULTS: The majority of nurses supported PAD and its legalization, with the greatest support being given when a suffering patient was involved. In the vignettes dealing with the nurse-patient relationship, oncology nurses were significantly less likely than nononcology nurses to agree with PAD but more likely to stay with their patients while the lethal drug was being given. Nononcology nurses were more supportive of legalization than oncology nurses. Religious nurses and nurses who observed religious traditions were significantly less likely to support PAD or vote for its legalization. CONCLUSION: Israeli nurses generally are supportive of PAD. However, oncology nurses were less likely to support its practice. In addition, the more religious nurses considered themselves, the less likely they were to support the practice. IMPLICATIONS FOR NURSING PRACTICE: Israeli nurses need to be made aware of the ethical, social, and legal implications of PAD and its legalization for the Israeli nursing profession. In addition, more cross-cultural research on attitudes toward PAD needs to be conducted.     

Osteoprogenitor cells within skeletal muscle.

The formation of ectopic bone within skeletal muscle is a widely observed phenomenon. However, the source of the osteoprogenitor cells responsible for ectopic bone formation remains unknown. This study was designed to test for osteogenic differentiation among cells isolated from skeletal muscle tissue. Different subpopulations of cells derived from an adult mouse skeletal muscle were tested for induction of alkaline phosphatase activity after exposure to bone morphogenetic protein-2 in vitro. A responsive subpopulation was identified, transduced with a retrovirus encoding for beta-galactosidase (Rv-lacZ) and an adenoviral construct encoding for one bone morphogenetic protein-2, and injected into the hindlimb of immune compromised (severe combined immunodeficient, or SCID) mice. The injected cells appeared to actively participate in the ectopic bone formation. The existence of lacZ-positive muscle-derived cells colocalized with osteocalcin-producing cells within lacunae of newly formed bone matrix suggests osteoblast and osteocyte differentiation. Although a specific cell was not isolated, these data support the contentions that osteoprogenitor cells reside within skeletal muscle and that muscle may represent a source other than bone marrow for the harvest of these cells.     

Gallium–tin alloys as a low melting point liquid metal for repetition-pulse-laser-induced high energy density state toward compact pulse EUV sources

Here, we show the easy-handling of a liquid gallium–tin alloy (Ga : Sn) as a laser target source for 13.5 nm light generation. The alloys have ∼30 °C freezing points according to a differential scanning calorimetry cooling process. A Nd:YAG laser (1064 nm, 1 ns, 7.1 × 10¹⁰ W cm⁻²) ablated the alloys, obtaining a similar extreme ultraviolet emission intensity to Sn despite a small quantity of Sn. Finally, we demonstrate a liquid metal alloy jet and droplets using a plastic nozzle for high-repetition target supply.

We show the near-room-temperature-handling of a liquid gallium–tin alloy (Ga:Sn) as a laser target source for 13.5 nm pulse repetition.

Liquid metals have generated interest in relation to electronics due to the possibilities of producing flexible circuitry, moldable parts, and stretchable electrodes.¹ Liquid metals can dissolve other metal ions, often further lowering the melting point through bond disruption.^1b In particular, gallium has shown strong potential as it exists readily in a liquid state at room temperature, with a non-oxygenated bulk and non-toxic properties. For example, gallium-based catalysts are exciting in terms of CO₂ reduction.^1cA cruder, but no less interesting, way of using liquid metals is in laser plasma generation. Laser plasma sources are of interest in fields such as extreme ultraviolet lithography (EUVL) and quantum beam generation.² EUVL generation is a process whereby a material, typically tin, is heated by a high-intensity laser pulse to ∼100 eV. The energy losses from the laser pulse (I_L) are excess heating to high ionization (I_ion), greater kinetic energy of ions and electrons (I_kin), and out-of-band radiation (I_oobrad) as follows:^2eI_L = I_kin + I_ion + I_rad + I_oobrad1In order to obtain the most favorable wavelength of 13.5 nm for the lithography optics, tin is the best element with the highest I_rad under optimized conditions.^2eThe light produced by this heating will be applied in the high volume manufacturing of semiconductors as a lithographic process. Currently, commercial EUVL sources are supplied as a test tool for lithography; powers at the intermediate focus are ever increasing (>125 W), and the source is highly available (>80%).³ However, more is needed from EUVL sources due to the need for higher throughput.⁴ Furthermore, practical issues remain problematic, such as the durability issue of the reflective optics.^4,5In addition to EUVL, compact EUV sources with different target sources, such as gas puff targets⁶ and low-density materials,⁷ are becoming attractive. These sources should be low cost, allowing exploration of different applications such as surface modification of materials⁸ and time-resolved ultraviolet photoelectron spectroscopy (UPS) studies, etc. By combining high-power laser compactness⁹ and emerging target materials and technologies,^7e,10 reliable quantum beam sources can be developed. Overall, laser plasma target materials play an important role in producing very high temperature plasmas, X-ray and higher quantum beam emission.To date, many works have focused on the technical optimization of EUV, such as the laser and target parameters.^10,11 However, optimizing the target source could be just as beneficial for EUV and other laser plasma sources; for example clever target design can improve laser conversion efficiency (CE).^11f This area is firmly established with the chemical synthesis of these low-density targets.^{7f,10,11b,11f} The plasma generated from well-defined low-density targets have lower self-reabsorption than full-density targets.^11a Dilution of tin is also an effective method for obtaining a high CE by-polymer,^11d and lithium dilution.^11f One criticism of minimum mass and well-defined low-density targets is that large laser systems would require a substantial design modification in order to be accommodated. However, an alternative dilution by a liquid metal droplet source would not suffer the same issues as liquid tin. This could be easily adapted to existing EUV design protocols, and should be considered for larger laser plasma sources. Furthermore, construction of new generations of EUV sources based on a low melting point liquid alloy would be simpler than liquid tin. Low melting point metals such as gallium or indium have caught the interest of EUV researchers.¹² One alloy that heavily utilizes gallium, commercially known as Galinstan®, is typically composed of Ga (62–95%), In (5–22%) and Sn (0–16%), and has a strong emission of 13.5 nm light due to the presence of Sn.^12a Therefore, Galinstan® could be highly desirable as a target source for EUVL given the very low reported melting point of −19 °C. However, low CE and the broad and flat shaped EUV spectrum due to the presence of indium (∼15/16 nm) and gallium (∼11/12 nm) restricts Galinstan® to metrology applications.^12b For EUV, the choice between utilization of gallium or indium is a decision for researchers. Such as a 50 : 50% Sn : In alloy has the same density as liquid Sn, and a melting point of ∼155 °C.¹³ On the other hand, gallium has a lower melting point than indium, meaning that alloys of gallium–tin could remain liquid at temperatures less than 100 °C. Although gallium has been mentioned on patents,¹⁴ there is a lack of accessible experimental data to assess the viability of gallium alloys as an EUV source.The aim of this work was to demonstrate that Ga : Sn alloys are an easy-handling liquid metal alternative to Sn as a laser plasma target source. Ga : Sn alloys of differing atomic (at%) ratios were synthesized, then characterized using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) with X-ray dispersive spectroscopy (EDS). A Nd:YAG laser (1 ns, 2 mJ) was used to generated EUV under similar conditions to previous work,¹⁵ with a grazing incidence spectrometer (GIS). As an example, we show that EUV emission intensity for the Ga : Sn alloy was equal to bulk Sn, depending on the alloy composition. The CE for the Ga : Sn alloy was also estimated in comparison with bulk tin using a calorimeter. We also show the emission properties of the alloy irradiated by 10 Hz exposure in order to demonstrate the potential as a practical and flexible laser plasma target source. Finally, our progress developing Ga : Sn jets and droplets is shown.DSC data shown in Fig. S1–S4^† exhibit consistency with the phase diagram reported;¹⁶ the endothermic peak on the liquidus and exothermic peaks at the solidus (27 °C), and supercooling solidus from the metastable state (–25 °C) are shown in

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation

Background

Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells).

Materials and methods

Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways.

Results

Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12).

Conclusions

LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.