Laser-assisted atom probe tomography of semiconductors: The impact of the focused-ion beam specimen preparation.

This paper demonstrates the increased light absorption efficiency of semiconducting atom probe tips resulting from focused-ion-beam (FIB) preparation. We use transmission electron microscopy to show that semiconducting tips prepared with FIB are surrounded with an amorphized shell. Photomodulated optical reflectance measurements then provide evidence that FIB-induced damage leads to an increase in both sub- and supra-bandgap light absorption efficiency. Using laser-assisted atom probe tomography (La-APT) measurements, we finally show that, for a nanoscale tip geometry, the laser-induced heating of a tip during La-APT is enhanced by the FIB preparation. We conclude that, upon supra-bandgap illumination, the presence of a FIB-amorphized surface dramatically increases the light-induced heat generation inside semiconducting tips during La-APT. Furthermore, we also deduce that, in the intriguing case of sub-bandgap illumination, the amorphization plays a crucial role in the unexpected light absorption.

Wet-chemical etching of atom probe tips for artefact free analyses of nanoscaled semiconductor structures.

We introduce an innovative specimen preparation method employing the selectivity of a wet-chemical etching step to improve data quality and success rates in the atom probe analysis of contemporary semiconductor devices. Firstly, on the example of an SiGe fin embedded in SiO2 we demonstrate how the selective removal of SiO2 from the final APT specimen significantly improves accuracy and reliability of the reconstructed data. With the oxide removal, we eliminate the origin of shape artefacts, i.e. the formation of a non-hemispherical tip shape, that are typically observed in the reconstructed volume of complex systems. Secondly, using the same approach, we increase success rates to ∼90% for the damage-free, 3D site-specific localization of short (250 nm), vertical Si nanowires at the specimen apex. The impact of the abrupt emitter radius change that is introduced by this specimen preparation method is evaluated as being minor using field evaporation simulation and comparison of different reconstruction schemes. The Ge content within the SiGe fin as well as the 3D boron distribution in the Si NW as resolved by atom probe analysis are in good agreement with TEM/EDS and ToF-SIMS analysis, respectively.

Atom probe tomography analysis of SiGe fins embedded in SiO2: Facts and artefacts.

We present atom probe analysis of 40nm wide SiGe fins embedded in SiO2 and discuss the root cause of artefacts observed in the reconstructed data. Additionally, we propose a simple data treatment routine, relying on complementary transmission electron microscopy analysis, to improve compositional analysis of the embedded SiGe fins. Using field evaporation simulations, we show that for high oxide to fin width ratios the difference in evaporation field thresholds between SiGe and SiO2 results in a non-hemispherical emitter shape with a negative curvature in the direction across, but not along the fin. This peculiar emitter shape leads to severe local variations in radius and hence in magnification across the emitter apex causing ion trajectory aberrations and crossings. As shown by our experiments and simulations, this translates into unrealistic variations in the detected atom densities and faulty dimensions in the reconstructed volume, with the width of the fin being up to six-fold compressed. Rectification of the faulty dimensions and density variations in the SiGe fin was demonstrated with our dedicated data treatment routine.

Optimal laser positioning for laser-assisted atom probe tomography.

Laser-assisted atom probe tomography is a material analysis method based on field evaporating ions from a tip-shaped sample by a combination of a standing electric field and a short (pico- or femtosecond) laser pulse. The laser-pulse thereby acts as a starting signal for a time-of-flight mass analysis of the ions whereby the thermal energy deposited in the tip by the laser pulse temporarily enables the evaporation of ions from the surface of the tip. Here we will use simulations of the laser absorption on a silicon tip to find the optimal position of the laser spot in order to maximize the mass resolution achieved during the experiments. We will confirm our simulations by showing that the experimentally observed mass resolution indeed changes as predicted by the simulations.

Light absorption in conical silicon particles.

The problem of the absorption of light by a nanoscale dielectric cone is discussed. A simplified solution based on the analytical Mie theory of scattering and absorption by cylindrical objects is proposed and supported by the experimental observation of sharply localized holes in conical silicon tips after high-fluence irradiation. This study reveals that light couples with tapered objects dominantly at specific locations, where the local radius corresponds to one of the resonant radii of a cylindrical object, as predicted by Mie theory.

Subtelomeric rearrangements in Polish subjects with intellectual disability and dysmorphic features.

Fluorescent in situ hybridization (FISH) was performed in 76 patients referred to our department because of intellectual disability and dysmorphic features that can be related to subtelomeric microaberrations. In all the patients, conventional cytogenetic methods revealed normal karyotype. Four (5.3%) subtelomeric rearrangements were detected by FISH: 2 subtelomeric 1p36 deletions, an unbalanced translocation involving chromosomes 1 and 12 with 1p36 deletion, and a de novo balanced translocation involving chromosomes 19 and 22. Thus, 3 cases of 1p36 subtelomeric deletion were found (3.95%). To confirm subtelomeric rearrangements in 2 patients, comparative genomic hybridization (CGH) was applied. Moreover, 3 cases of polymorphism without phenotypic effects were found: in 2 patients, the polymorphism involved the long arm of chromosome 2 (maternal derivative in both patients), while in the third patient, a polymorphism of the long arm of chromosome 7 was diagnosed. The latter polymorphism was also found in the patient's mother and grandfather.

Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer.

PURPOSE: Advanced disseminated prostate cancer is highly resistant to cytotoxic chemotherapy. We identified proteins that may be involved in multidrug resistance in clinical prostate cancer. Expression of these proteins was examined in the context of tumor progression. MATERIALS AND METHODS: Paraffin embedded, formalin fixed prostate cancer specimens from archival sources of 3 distinct patient groups were examined. These groups were clearly distinct with regard to pathological stage and responsiveness to antihormonal therapy. Group 1 consisted of patients with organ confined prostate cancer treated with radical prostatectomy (early pathological stage T2N0M0). Group 2 patients had disseminated, early advanced prostate cancer and were treated with transurethral prostatic resection for urinary obstruction before receiving antihormonal therapy. Group 3 patients had disseminated prostate cancer with relapse despite antihormonal treatment (late advanced prostate cancer) and they underwent transurethral prostatic resection to relieve the symptoms of urinary obstruction. Immunohistochemical study was done to detect P-glycoprotein, multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, Bax, topoisomerase I, IIalpha and IIbeta, and Ki-67. RESULTS: Advanced tumors were distinguished from locally confined tumors because they exhibited significantly higher histological grade and proliferative activity. The expression of multidrug resistance associated protein, p53, topoisomerase IIalpha, Ki-67 and topoisomerase IIbeta was significantly related to a higher Gleason sum score. The number of cases expressing multidrug resistance associated protein, lung resistance protein, glutathione-S-transferase pi, p53, Bcl-2, topoisomerase IIalpha and Ki-67 was significantly increased in the group with advanced disseminated prostate cancer. Topoisomerase I and IIbeta were homogeneously and highly expressed at all stages of prostate cancer progression, while P-glycoprotein was not expressed in any tumors regardless of the patient group. CONCLUSIONS: Up-regulation of the expression of the drug transporters multidrug resistance associated protein and lung resistance protein, detoxifying enzyme glutathione-S-transferase pi, and apoptosis inhibiting proteins Bcl-2 and p53 may be an explanation of the resistance of disseminated progressive prostate cancer to chemotherapy. As shown by the up-regulation of Ki-67 and topoisomerase IIalpha, increased proliferation reflects the aggressiveness of metastatic prostate cancer. Research on agents that counteract multidrug resistance mechanisms and may sensitize prostate carcinoma to cytotoxic chemotherapy may possibly lead to more effective treatment of progressive disseminated prostate cancer.

Identification, characterization and purification of the lantibiotic staphylococcin T, a natural gallidermin variant.

Staphylococcin T (StT), an antibacterial agent produced by a Staphylococcus cohnii T strain, was purified to homogeneity by ammonium sulphate precipitation, gel filtration, cation exchange and fast performance liquid chromatography (FPLC). The final yield was about 20%, and over a 1000-fold increase in the specific activity was obtained. Mass determination (2166 Da), amino acid sequencing (Ile-Ala-Xaa-Lys-Phe-Leu-Xaa-Xaa-Pro-Gly-Xaa-Ala-Lys-block) and DNA sequencing demonstrated that StT is identical to gallidermin, a lanthionine-containing antimicrobial peptide. StT has a broad spectrum of bactericidal activity against Gram-positive and some Gram-negative bacteria. StT appears to damage cell membrane, and as a result causes an efflux of ions and an immediate block in macromolecular synthesis. Moreover, electron microscopic observations reveal morphological changes, with a loss of ribosomes and condensation of the nucleoid DNA. These changes are followed by a dissolution of the cell contents resulting in a bacterial ghost composed of seemingly intact cell walls with remnants of the cytoplasmic membrane and internal structure. Since StT exhibits antimicrobial activity especially against the Staphylococcus species, this compound may be of use in the treatment of staphylococcal infections.

The prognostic value of pretreatment expression of androgen receptor and bcl-2 in hormonally treated prostate cancer patients.

PURPOSE: We determined the prognostic value of oncoprotein bcl-2 and androgen receptor expression in pretreatment transurethral resection specimens of hormonally treated prostate cancer patients. MATERIALS AND METHODS: A total of 68 pretreatment transurethral resection specimens, 30 radical prostatectomy specimens and 21 palliative transurethral resection specimens with androgen independent prostate cancer was stained with a monoclonal antibody against bcl-2. Androgen receptor immunohistochemistry was performed on pretreatment transurethral resection specimens only. Results were scored semiquantitatively and were correlated with tumor stage and grade and with the occurrence of clinical progression or tumor related death. RESULTS: Bcl-2 expression by adenocarcinoma cells was found in 32, 17 and 24% of pretreatment transurethral resection, radical prostatectomy and palliative transurethral resection specimens, respectively. The bcl-2 scores did not correlate with tumor stage or grade. Androgen receptor was expressed in 88% of pretreatment transurethral resection specimens. Androgen receptor scores were marginally related to tumor grade, but not to tumor stage. A prognostic value of bcl-2 or androgen receptor in pretreatment transurethral resection specimens was not found. When a combined bcl-2/androgen receptor score was used, this parameter was an independent prognostic marker to predict clinical progression with Gleason grade and stage classification. Gleason grade was the only independent prognostic marker to predict tumor related death. CONCLUSIONS: The expression of bcl-2 and androgen receptor in pretreatment prostate cancer specimens is not related to the prognosis of hormonally treated prostate cancer. Bcl-2 expression is not increased in endocrine therapy resistant prostate cancer. Surprisingly, a combined bcl-2/androgen receptor score acts as an independent prognosticator for clinical progression.

The prognostic value of neuroendocrine differentiation in adenocarcinoma of the prostate in relation to progression of disease after endocrine therapy.

PURPOSE: We evaluated the prognostic impact of neuroendocrine differentiation in prostate cancer with regard to the onset of endocrine therapy failure. MATERIALS AND METHODS: A retrospective study was performed on 72 transurethral resection specimens from patients who subsequently underwent endocrine therapy for prostate cancer and were followed for 44 to 95 months. Progression-free interval was recorded. Distribution pattern and proportion of neuroendocrine cells were examined in transurethral resection specimens. Neuroendocrine cells were identified based on immunoreactivity for chromogranin A. RESULTS: Of 32 patients with progressive disease 27 died of prostate cancer. Chromogranin A positive cells were found in 40 of the 72 prostate cancers (55%). In a Cox proportional hazards analysis neuroendocrine differentiation of the tumor showed a negative correlation with progression-free survival (p = 0.022), which proved to be independent of the Gleason score (p < 0.001). CONCLUSIONS: Our results support the view that neuroendocrine differentiation in prostatic adenocarcinomas is a prognostic factor for progressive disease under subsequent endocrine therapy. This prognosticator acts independently of tumor grade.

A randomized study on the effect of bladder irrigation with povidone-iodine before removal of an indwelling catheter.

We have evaluated the effect of povidone-iodine (PVP-I) bladder irrigation prior to catheter removal on subsequent bacteriuria. Of 264 patients, 138 received PVP-I irrigation and 126 were controls. Both groups were similar with respect to duration of catheterization and bacteriuria before removal of the catheter. Of 497 cultures taken after catheter removal 99 (20%) were positive. This included 52 of 233 in the control group (22%) and 47 of 264 in the study group (18%). Patients with positive cultures had a significantly longer period of catheterization. Our trial did not demonstrate that PVP-I bladder irrigation before catheter removal reduces subsequent bacteriuria.

Phase 1/2 study of intravesical epirubicin in patients with carcinoma in situ of the bladder.

A total of 34 patients with grade 3 carcinoma in situ of the bladder entered a phase 1/2 study with epirubicin to examine the rate of antitumor activity, the type and frequency of local side effects, and the absorption and recovery rates. The selected doses were 30, 50 and 80 mg. Of the patients 22 were evaluable for report of treatment results. A total of 16 patients had a complete remission proved by biopsy and conversion of urine cytology findings. Mean duration of complete remission was 22.4 months (range 7+ to 50+ months). After a mean followup of 35.3 months (range 14 to 59 months) 8 of 16 patients were still in complete remission, 3 died of a myocardial infarction, 3 had recurrent grade 3 carcinoma in situ, 2 had increase to a higher T category (stages T2 and T4a), and 2 had recurrent papillary stage Ta, grade 2 (1) and stage T1, grade 2 (1) transitional cell carcinoma of the bladder. Six of the 22 patients had no response to 1 or 2 treatment courses with a higher dose. Plasma concentrations of epirubicin after instillation were close to the detection limit of the assay (0.5 to 2.0 ng/ml. plasma).

Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study.

The possible relationship between changes in peripheral hormone levels and the occurrence of prostatic pathology was studied in a case-control study, involving estimation of various plasma hormones in 368 Dutch and 258 Japanese men, who were grouped as controls and patients with benign prostatic hyperplasia, focal prostatic carcinoma, or clinically evident prostatic carcinoma. Results of a number of previous, smaller studies concerning interrelationships between hormone levels in elderly men were confirmed within the Dutch and Japanese groups. Plasma levels of testosterone and estradiol were significantly lower in the Japanese men, when compared with those in Dutch men. Probably as a result of this difference in testosterone levels, the ratio between serum levels of testosterone and sex hormone-binding globulin (SHBG) was decreased in the Japanese men, while the ratio between the concentrations of dihydrotestosterone and testosterone was increased. These differences were also found when results from Japanese subgroups (controls and patients with prostate pathology) were compared with those from the Dutch subgroups. There were no significant differences in plasma androgen levels between Japanese or Dutch prostate cancer cases and their respective control subgroups. These findings do not support a correlation between the lower plasma testosterone levels and a lower incidence of prostate cancer in the Japanese men. Furthermore, no significant differences were found between salivary levels of testosterone or the ratio between testosterone and SHBG in the various Dutch subgroups. In Japanese benign prostatic hyperplasia patients, the testosterone to SHBG ratio was significantly increased. In conclusion, the results of this retrospective, cross-sectional study do not indicate that hormonal levels play a primary role in the origin or promotion of prostatic abnormalities. The finding of a lower plasma testosterone in the Japanese men, however, remains suggestive, warranting a more extensive prospective study.

Evaluation of prostate-specific antigen and prostatic acid phosphatase in untreated prostatic carcinoma and benign prostatic hyperplasia.

Prostate specific acid phosphatase (PAP) (Abbott, solid-phase enzyme immunoassay) and prostate specific antigen (PSA) (Hybritech, immunoradiometric assay) were determined in 162 newly diagnosed prostatic carcinoma patients, 187 patients with benign prostatic hyperplasia (BPH) and 127 controls. The upper limit of normal in controls for PAP was 2.2 micrograms/l and for PSA 5.0 micrograms/l. In the BPH group PAP was raised in 21%, for PSA in 41%. When the cut-off level of PSA was raised to 10.0 micrograms/l, 20% of BPH patients had an increased level. PSA was superior to PAP for the detection of prostatic cancer in all stages. Of the 162 patients with prostatic carcinoma, 88 had localised diseases and 74 had metastatic spread. PSA and PAP levels increased with each advancing clinical stage. PAP was elevated in 35% of the patients with cancer confined to the prostate. PSA in 69%. (PSA level 10.0 micrograms/l: 57%). In those patients with metastatic spread PAP was elevated in 77% compared with 96% for PSA. (PSA level 10.0 micrograms/l: 92%). The combined use of PSA and PAP does not give a greater accuracy in the screening of prostate cancer when compared with the sole use of PSA. PAP was elevated in only 4 patients when PSA was normal. In the BPH group there was no proven effect of micturition, frequency or residual urine on the SPA level. However, in this group infection may cause a rise in the PSA level.

[A comparison between prostate-acid-phosphatase and prostate-specific antigen in the diagnosis of prostatic carcinoma]. / Een vergelijking tussen prostaat-zure-fosfatase en prostaatspecifiek antigeen bij de diagnostiek van het prostaatcarcinoom.

A comparison is made of prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) in the diagnosis of prostatic carcinoma. In a retrospective study PAP ans PSA were compared in 127 normal elderly men, in 187 patients with benign prostatic hyperplasia (BPH) and in 162 patients with untreated prostatic carcinoma. In the control group a normal value of 2.2 micrograms/l was found for PAP and 5.0 micrograms/l for PSA. In 41% of BPH patients the PSA level was higher than 5.0 micrograms/l. Because of this substantial percentage a cut-off value of 10 micrograms/l was used instead of 5.0 micrograms/l. In the BPH group 20% had a PSA level over 10 micrograms/l and 21% a PAP over 2.2 micrograms/l. Of the carcinoma patients without metastasis 57% had a PSA level over 10 micrograms/l and of those with metastatic disease, 92%. For PAP these percentages were 35 and 77, respectively. It is concluded that PSA is a more sensitive tumour marker than PAP.

Evaluation of prostate-specific antigen in untreated prostatic carcinoma.

A study was performed on 290 men to compare the level of serum prostate-specific antigen (PSA) in controls, patients with benign prostatic hyperplasia (BPH) and patients with prostatic cancer. The upper limit of normal was 5.0 micrograms/l as determined in 110 elderly hospitalized males (mean age 62 years) without urological complaints. Of the 106 patients with BPH, 33% had raised values above 5.0 micrograms/l. Values above 10 micrograms/l were found in 18 BPH patients. A positive correlation was found between prostate volume (grams of tissue removed during transurethral resection) and preoperative PSA levels (r = 0.55, n = 106, p less than 0.001). PSA levels above 10 micrograms/l were found in 4% of BPH patients with a prostate volume of less than 20 g (n = 54), in contrast with 45% of patients with a prostate volume above 40 g (n = 20). The sensitivity of this PSA assay (cutoff level 10 micrograms/l) as established in 74 prostate carcinoma patients was 31% for category T0 (n = 13), 56% for category T1-2 (n = 16), 75% for category T3-4 (n = 20) and 100% for category M1 or N1-4 (n = 25). In an earlier study prostatic acid phosphatase (PAP) was measured in these same samples. PSA appeared to be much more sensitive than PAP. Seventeen of the 74 prostatic carcinoma patients (23%) had normal PAP levels but their PSA values were raised above 10 micrograms/l, while in only 2 patients an increased PAP level was combined with a normal PSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption of epi-doxorubicin after intravesical administration in patients with in situ transitional cell carcinoma of the bladder.

Nine patients with in situ bladder cancer (TIS) were treated by intravesical instillation of epi-doxorubicin (epi-DOX). The amount of anthracycline in 1 ml plasma was in the nanogram range. 78.9 +/- 12.0% and 84.2 +/- 10.6% of the administered dose (30 and 50 mg, respectively) could be recovered.