A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer.

PURPOSE: KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. EXPERIMENTAL DESIGN: 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). RESULTS: The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. CONCLUSIONS: The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.

Note: Measurements of fast electrons in the TORE-SUPRA tokamak by means of modified Cherenkov-type diamond detector.

The Note reports on experimental studies of ripple born fast electrons within the TORE-SUPRA facility, which were performed by means of a modified measuring head equipped with diamond detectors designed especially for recording the electron-induced Cherenkov radiation. There are presented signals produced by fast electrons in the TORE-SUPRA machine, which were recorded during two experimental campaigns performed in 2010. Shapes of these electron-induced signals are considerably different from those observed during the first measurements carried out by the prototype Cherenkov probe in 2008. An explanation of the observed differences is given.

Development of a diagnostic technique based on Cherenkov effect for measurements of fast electrons in fusion devices.

A diagnostic technique based on the Cherenkov effect is proposed for detection and characterization of fast (super-thermal and runaway) electrons in fusion devices. The detectors of Cherenkov radiation have been specially designed for measurements in the ISTTOK tokamak. Properties of several materials have been studied to determine the most appropriate one to be used as a radiator of Cherenkov emission in the detector. This technique has enabled the detection of energetic electrons (70 keV and higher) and the determination of their spatial and temporal variations in the ISTTOK discharges. Measurement of hard x-ray emission has also been carried out in experiments for validation of the measuring capabilities of the Cherenkov-type detector and a high correlation was found between the data of both diagnostics. A reasonable agreement was found between experimental data and the results of numerical modeling of the runaway electron generation in ISTTOK.

Characteristics of four-channel Cherenkov-type detector for measurements of runaway electrons in the ISTTOK tokamak.

A diagnostics capable of characterizing the runaway and superthermal electrons has been developing on the ISTTOK tokamak. In previous paper, a use of single-channel Cherenkov-type detector with titanium filter for runaway electron studies in ISTTOK was reported. To measure fast electron populations with different energies, a prototype of a four-channel detector with molybdenum filters was designed. Test-stand studies of filters with different thicknesses (1, 3, 7, 10, 20, 50, and 100 µm) have shown that they should allow the detection of electrons with energies higher than 69, 75, 87, 95, 120, 181, and 260 keV, respectively. First results of measurements with the four-channel detector revealed the possibility to measure reliably different fast electrons populations simultaneously.

Cherenkov-type diamond detectors for measurements of fast electrons in the TORE-SUPRA tokamak.

The paper presents a schematic design and tests of a system applicable for measurements of fast electron pulses emitted from high-temperature plasma generated inside magnetic confinement fusion machines, and particularly in the TORE-SUPRA facility. The diagnostic system based on the registration of the Cherenkov radiation induced by fast electrons within selected solid radiators is considered, and electron low-energy thresholds for different radiators are given. There are some estimates of high thermal loads, which might be deposited by intense electron beams upon parts of the diagnostic equipment within the TORE-SUPRA device. There are some proposed measures to overcome this difficulty by the selection of appropriate absorption filters and Cherenkov radiators, and particularly by the application of a fast-moving reciprocating probe. The paper describes the measuring system, its tests, as well as some results of the preliminary measurements of fast electrons within TORE-SUPRA facility.

Use of Cherenkov-type detectors for measurements of runaway electrons in the ISTTOK tokamak.

Gas, fluid, or solid Cherenkov-type detectors have been widely used in high-energy physics for determination of parameters of charged particles, which are moving with relativistic velocities. This paper presents experimental results on the detection of runaway electrons using Cherenkov-type detectors in the ISTTOK tokamak discharges. Such detectors have been specially designed for measurements of energetic electrons in tokamak plasma. The technique based on the use of the Cherenkov-type detectors has enabled the detection of energetic electrons (energies higher than 80 keV) and determination of their spatial and temporal parameters in the ISTTOK discharges. Obtained experimental data were found in adequate agreement to the results of numerical modeling of the runaway electron generation in ISTTOK.

Molecular analysis of Y chromosome long arm structural instability in patients with gonadal dysfunction.

We have performed cytogenetic and molecular analyses of 45,X mosaics involving structurally abnormal Y chromosomes. Karyotypes were performed by standard cytogenetic methods and, in some cases, by fluorescence in situ hybridization, to distinguish monocentric and dicentric chromosomes. In addition, the deletions of Yq have been mapped using Southern blotting and polymerase chain reaction analysis. This paper provides additional information on the analysis of Y chromosome aberrations, and suggests that the stability of the Y chromosome in these instances is related to the site of the break point on Yq.

[Neurological aspects of two patients with non-mosaic and mosaic polysomy of the X and Y chromosomes]. / Aspekty neurologiczne u dwóch chorych z niemozaikowa i mozaikowa polisomia chromosomów X i Y.

Clinical features were compared of a patient with the 48,XXYY karyotype and a case of 47,XXY/48,XXYY mosaicism. In the former patient tremor of the upper extremities of unclear aetiology was present. In both cases epilepsy was suspected. Similarly as in other cases of 48,XXYY karyotype the first patient had skeletal anomalies, abnormalities of dermatoglyphics and personality changes. These features are rarely found in Klinefelter syndrome. The differences in relation to the syndrome were less evident in the case of mosaicism 47,XXY/48,XXYY.

[The state of the eye in children with Down syndrome caused by trisomy 21 translocation]. / Stan narzadu wzroku u dzieci z zespolem Down'a wywolanym trisomia 21 translokacyjna.

This paper presents results ophthalmological examination of 16 children with translocation trisomy 21/21 and 14/21 selected among group 192 patients with Down syndrome confirmed by cytogenetic examination. Ophthalmological state in the children with chromosomal aberration and simple trisomy 21 was similar.

Cytogenetic and molecular identification of a de novo direct duplication of the long arm of chromosome 4(q21.3-->q31.3).

We report on a 3-year-old boy with moderate developmental retardation, microcephaly, and malformations of ears, lids, mouth, and thumbs. Cytogenetic analysis demonstrated a direct duplication of chromosome subregion 4(q21.3-->q31.3). Confirmation of this specific rearrangement was performed by fluorescent in situ hybridization (FISH) with a chromosome painting probe and by means of quantitative Southern hybridization with DNA probes localized within the chromosome 4 region presumed to be duplicated.

Two familial 9;17 translocations with variable effect on male carriers fertility.

Two similar, but not identical, familial reciprocal translocations are described. In the first family, four sterile males inherited reciprocal translocation t(9;17)(q11'3) of maternal origin. In the second family, with the male fertility not impaired, reciprocal t(9;17)(q11;q11) was observed in four members of the family.

De novo direct tandem duplication of the short arm of chromosome 7(p21.1-p14.2).

We report on a 6-year-old boy with moderate developmental retardation and unusual dermatoglyphics. Cytogenetic analysis demonstrated a duplication of chromosome sub-region 7p21.2-p14.2. Confirmation of the specific duplicated region was determined by quantitative Southern blotting by using a DNA fragment previously localized to the portion of chromosome 7 thought to be duplicated. This patient did not have the internal malformations seen with other dup(7p) patients.

[Cytological examination of the amniotic fluid in normal pregnancy and in cases of fetal central nervous system abnormalities]. / Badania cytologiczne plynu owodniowego w ciazy fizjologicznej oraz w przypadkach wad centralnego ukladu nerwowego u plodu.

Cytological and biochemical investigations were carried out on 60 samples of amniotic fluid obtained from 30 pregnant women with risk for development of fetal central nervous abnormality (FCNA) and 30 pregnant women in whom prenatal diagnosis was indicated for other reasons (control group). Cytological evaluation was done in an interference-polarization Nomarski microscope evaluating the cells in direct preparation and after staining with neutral red. Parallelly with cytological evaluation alpha-1-fetoprotein (AFP) and acetylcholinesterase (AChE) were determined in amniotic fluid. In three cases with open neural tube anomaly characteristic cells with strongly puckered and vacuolized cytoplasmic membranes were found. In these cases the levels of AFP and AChE exceeded the normal range. In two cases of closed abnormalities of the central nervous system diagnosed by ultrasonography no abnormalities were note by cytological and biochemical methods. The study confirmed the usefulness of the cytological examination of amniotic fluid, as a method supplementing biochemical and ultrasonographic investigations as part of prenatal diagnosis.

Two mosaic cases with nonfluorescent Y chromosome analysed with Y-specific DNA probes.

Two cases of a nonfluorescent Y (Ynf) chromosome were diagnosed: one in a male, the other in a female. Both had similar complex mosaic chromosome constitutions with a 45,X cell line. DNA studies were applied in both cases for verification of the cytogenetic diagnosis. The results on the two patients were compared with data obtained from seven healthy men (46,XY), three healthy women (46,XX), two females with 46,XY karyotype, and from cell lines with 49,XXXXY and 48,XXXX chromosome constitution. The highly repetitive Y-specific DNA sequences located in the heterochromatic region of the long arm were absent in these patients. Differences in the composition of the euchromatic part of the Y chromosome were demonstrable in both patients. The highly repetitive Y-specific DNA sequences located in the heterochromatic region of the long arm were absent in these patients. Differences in the composition of the euchromatic part of the Y chromosome were demonstrable in both patients. The suggestion that the Ynf chromosome originates from a dicentric Y chromosome cannot be accepted as a complete explanation of the phenomenon, as it probably involves more complex molecular alterations of the abnormal Y chromosome. The presence of Ynf is associated with the presence of a 45,X cell line more often than in cases of simple Y chromosome deletions with the breakpoint localized in or below the Y euchromatin/heterochromatin junction.

Regular trisomy 21 not accompanied by increased copper-zinc superoxide dismutase (SOD1) activity.

The Cu-Zn superoxide dismutase (SOD1) activity was estimated in red blood cells in children with regular trisomy 21. We report patients displaying typical Down syndrome clinical features and with SOD1 activity in the normal range.

The antimitotic effect of bromocriptine on human fibroblasts.

The effect of bromocriptine on tritiated thymidine incorporation into nuclei of human fibroblasts has been investigated. A dose--dependent decrease of the labelling index has been found. This observation suggests that the antimitotic action of bromocriptine is a more general phenomenon not restricted to the adenohypophysial cells.