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Biomedical subjects

Sabine Mai

Publications and source records attributed to Sabine Mai.

At least 19 recordsLinked to original sources
PubMed2007

Image-guided in vivo dosimetry for quality assurance of IMRT treatment for prostate cancer.

PURPOSE: In external beam radiotherapy (EBRT) and especially in intensity-modulated radiotherapy (IMRT), the accuracy of the dose distribution in the patient is of utmost importance. It was investigated whether image guided in vivo dosimetry in the rectum is a reliable method for online dose verification. METHODS AND MATERIALS: Twenty-one dose measurements were performed with an ionization chamber in the rectum of 7 patients undergoing IMRT for prostate cancer. The position of the probe was determined with cone beam computed tomography (CBCT). The point of measurement was determined relative to the isocenter and relative to an anatomic reference point. The dose deviations relative to the corresponding doses in the treatment plan were calculated. With an offline CT soft-tissue match, patient positioning after ultrasound was verified. RESULTS: The mean magnitude +/- standard deviation (SD) of patient positioning errors was 3.0 +/- 2.5 mm, 5.1 +/- 4.9 mm, and 4.3 +/- 2.4 mm in the left-right, anteroposterior and craniocaudal direction. The dose deviations in points at corresponding positions relative to the isocenter were -1.4 +/- 4.9% (mean +/- SD). The mean dose deviation at corresponding anatomic positions was 6.5 +/- 21.6%. In the rare event of insufficient patient positioning, dose deviations could be >30% because of the close proximity of the probe and the posterior dose gradient. CONCLUSIONS: Image-guided dosimetry in the rectum during IMRT of the prostate is a feasible and reliable direct method for dose verification when probe position is effectively controlled.

Feasibility Studies↗
PubMed2006

Formation of non-random extrachromosomal elements during development, differentiation and oncogenesis.

Extrachromosomal elements (EEs) were first discovered as minute chromatin bodies [Cox et al. Minute chromatin bodies in malignant tumors of childhood. Lancet 1965;62:55-8], and subsequently characterized as small circular DNA molecules physically separated from chromosomes. They include episomes, minichromosomes, small polydispersed DNAs or double minutes. This review focuses on eukaryotic EEs generated by genome rearrangements under physiological or pathological conditions. Some of those rearrangements occur randomly, but others are strictly non-random, highly regulated, and involve specific chromosomal locations (V(D)J-recombination, telomere maintenance mechanisms, c-myc deregulation). The multiple mechanisms of EEs formation are strongly interconnected and frequently linked to gene amplification. Identification of genes located on EEs will undoubtedly allow a better understanding of genome dynamics and oncogenic pathways.

Animals↗
PubMed2006

Binding of multivalent CD147 phage induces apoptosis of U937 cells.

CD147 is a broadly expressed cell-surface molecule and serves as a signaling receptor for extracellular cyclophilins. CD147 also appears to interact with immune cells, but its counter-receptor on these cells has not been clearly described. In the present report, we displayed multiple copies of the CD147 extracellular domain (CD147Ex) on VCSM13 phage to study the interaction of CD147 with its ligand. Recognition of phage containing fusion protein of CD147Ex and gpVIII (CD147Ex phage) by four different anti-CD147 mAbs indicated that at least parts of the CD147 are properly folded. Specific binding of CD147Ex phage to various cell types was demonstrated by flow cytometry. Morphological changes, however, were observed only in U937, a monocytic cell line, after 24 h incubation with multivalent CD147Ex phage. After 48 h, U937 cell propagation ceased. Staining with annexin V and the presence of cleaved caspase-3 indicated that many of the CD147Ex phage-treated cells had lost viability through apoptotic cell death. The above results suggest that CD147 induces apoptosis in U973 cells and that at least a portion of this cell death program involves a caspase-dependent pathway.

Annexin A5↗
PubMed2006

ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency.

BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1(delta11/delta11)) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca1(delta11/delta11)p53+/- mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca1(delta11/delta11) mice to escape from embryonic lethality. Compared to Brca1(delta11/delta11)p53+/- mice, lifespan of Brca1(delta11/delta11)Chk2-/- mice was remarkably extended. Analysis of Brca1(delta11/delta11)Chk2-/- mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(delta11/delta11)Chk2-/- female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer.

Aging, Premature↗
PubMed2006

The significance of telomeric aggregates in the interphase nuclei of tumor cells.

Telomeres are TTAGGG repetitive motifs found at the ends of vertebrate chromosomes. In humans, telomeres are protected by shelterin, a complex of six proteins (de Lange [2005] Genes Dev. 19: 2100-2110). Since (Müller [1938] Collecting Net. 13: 181-198; McClintock [1941] Genetics 26: 234-282), their function in maintaining chromosome stability has been intensively studied. This interest, especially in cancer biology, stems from the fact that telomere dysfunction is linked to genomic instability and tumorigenesis (Gisselsson et al. [2001] Proc. Natl. Acad. Sci. USA 98: 12683-12688; Deng et al. [2003] Genes Chromosomes Cancer 37: 92-97; DePinho and Polyak [2004] Nat. Genetics 36: 932-934; Meeker et al. [2004] Clin. Cancer Res. 10: 3317-3326). In the present overview, we will discuss the role of telomeres in genome stability, recent findings on three-dimensional (3D) changes of telomeres in tumor interphase nuclei, and outline future avenues of research.

Animals↗
PubMed2006

Frameless stereotactic radiosurgery of a solitary liver metastasis using active breathing control and stereotactic ultrasound.

BACKGROUND AND PURPOSE: Radiosurgery of liver metastases is effective but a technical challenge due to respiration-induced movement. The authors report on the initial experience of the combination of active breathing control (ABC) with stereotactic ultrasound (B-mode acquisition and targeting [BAT]) for frameless radiosurgery. PATIENTS AND METHODS: A patient with a solitary, inoperable liver metastasis from cholangiocellular carcinoma is presented (Figure 4). ABC (Figure 3) was used for tumor/liver immobilization. Tumor/liver position was controlled and corrected using ultrasound (BAT; Figure 1). The tumor was irradiated with a single dose of 24 Gy. RESULTS: Using ABC, the motion of the tumor was significantly reduced and the overall positioning error was < 5 mm (Figure 2). BAT allowed a rapid localization of the lesion during breath hold which could be performed without difficulties for 20 s. Overall treatment time was acceptable (30 min). CONCLUSION: Frameless stereotactic radiotherapy with the combination of ABC and BAT allows the delivery of high single doses to targets accessible to ultrasound with high precision comparable to a frame-based approach.

Aged↗
PubMed2006

Evaluation of possible prostate displacement induced by pressure applied during transabdominal ultrasound image acquisition.

BACKGROUND AND PURPOSE: For accurate positioning of the prostate in external radiotherapy, transabdominal ultrasound localization and positioning systems are available. Reports have stated that probe pressure applied during image acquisition causes clinically relevant prostate displacement. The aim of this study was to investigate the prostate displacement due to the pressure applied during transabdominal ultrasound image acquisition with the BAT ultrasound system. MATERIAL AND METHODS: For ten patients who had undergone iodine-125 seed implantation for brachytherapy of prostate cancer, X-ray simulations were performed before and during ultrasound image acquisition. The iodine seeds are visible on the X-ray images, representing the position of the prostate. The simulator's crosshair, indicating the isocenter, was used as reference coordinate system. For each patient the change in prostate position was calculated based on the seed positions during and after ultrasound examination. RESULTS: A maximum displacement of the prostate of 2.3 mm in anteroposterior and 1.9 mm in craniocaudal direction and a rotational change of up to 2.5 degrees were observed. If the system was not handled correctly and too much pressure was applied, a shift of the prostate of up to 10 mm could be induced. CONCLUSION: Compared to the prostate displacement due to changes in rectal filling, which according to Crook et al. can be as much as 1.7 cm, the maximum displacement of less than 0.3 cm caused by the probe pressure is negligible. However, proper education of the staff and preparation of the patient are essential for the safe use of the system.

Brachytherapy↗
PubMed2005

Oncogenic remodeling of the three-dimensional organization of the interphase nucleus: c-Myc induces telomeric aggregates whose formation precedes chromosomal rearrangements.

The three-dimensional (3D) organization of the normal interphase nucleus permits the regulated completion of transcription and replication and assures proper chromosome organization. Aberrations from the normal 3D structural order of the nucleus are found in tumor cells. When examining the 3D organization of telomeres in nuclei of normal and tumor cells, we found that telomeres of normal nuclei do not overlap, while telomeres of tumor cells form aggregates of various numbers and sizes. To understand how such changes occur and what their implications are we have recently examined the role of the oncoprotein c-Myc in inducing changes in the 3D nuclear organization of telomeres. We found that c-Myc remodels the organization of telomeres and chromosomes in the interphase nucleus. It induces the formation of telomeric aggregates and fusions that are followed by breakage-bridge fusion cycles, and lead to the onset of chromosomal rearrangements that are typical of tumor cells.

Animals↗
PubMed2005

c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus.

In previous work, we showed that telomeres of normal cells are organized within the 3D space of the interphase nucleus in a nonoverlapping and cell cycle-dependent manner. This order is distorted in tumor cell nuclei where telomeres are found in close association forming aggregates of various numbers and sizes. Here we show that c-Myc overexpression induces telomeric aggregations in the interphase nucleus. Directly proportional to the duration of c-Myc deregulation, we observe three or five cycles of telomeric aggregate formation in interphase nuclei. These cycles reflect the onset and propagation of breakage-bridge-fusion cycles that are initiated by end-to-end telomeric fusions of chromosomes. Subsequent to initial chromosomal breakages, new fusions follow and the breakage-bridge-fusion cycles continue. During this time, nonreciprocal translocations are generated. c-Myc-dependent remodeling of the organization of telomeres thus precedes the onset of genomic instability and subsequently leads to chromosomal rearrangements. Our findings reveal that c-Myc possesses the ability to structurally modify chromosomes through telomeric fusions, thereby reorganizing the genetic information.

Animals↗
PubMed2005

Uncoupling of genomic instability and tumorigenesis in a mouse model of Burkitt's lymphoma expressing a conditional box II-deleted Myc protein.

Burkitt's lymphomas (BL) are characterized by the constitutive expression of c-Myc protein. In total, 50-60% of all BL cells carry mutant c-Myc proteins. Using a mouse model of spontaneously immortalized pro-B-lymphocytes (Ba/F3), we have investigated genomic instability mediated by the conditional expression of either wild-type (WT) or deletion box II Delta106-Myc proteins. We found that both proteins mediate common as well as differing types of chromosomal rearrangements as documented by spectral karyotyping (SKY). A higher level of genomic instability is induced by the Delta106-Myc protein. To examine the tumorigenic potential of WT or Delta106-driven Ba/F3 cells, in vivo tumorigenesis studies were performed in SCID mice. Under the experimental conditions of this study, WT but not Delta106-Myc expressing Ba/F3 cells triggered tumorigenesis in SCID mice. Therefore, the genomic instability phenotype induced by Delta106-Myc can be genetically uncoupled from its tumorigenic potential.

Animals↗
PubMed2005

Cyclin D expression in chronic lymphocytic leukemia.

Although the majority of circulating leukemic cells in chronic lymphocytic leukemia (CLL) are in G0/early G1, recent studies have shown that these cells have undergone multiple cell divisions. In this study, we have determined whether there are abnormalities in cell cycle control in CLL by examining the three cyclin D isoforms in 43 patients and correlating the findings with clinical features. Cyclin D mRNA was measured by a sensitive RNase protection assay and the order of expression in CLL cells was D3 > D2 > D1. The mean cyclin D1 and D3 mRNA levels were 4 to 6-fold higher in CLL cells than in normal peripheral blood B cells. In contrast, the levels of cyclin D2 mRNA were similar in CLL and normal B cells. Expression of the cyclin D isoforms was two- to four-fold greater in normal T cells than B cells, and the order of expression for both cell types was D2 > D3 > D1. The relative overexpressions of cyclins D1 and D3 in CLL were unrelated to gene amplification, as assessed by Southern blotting, but structural changes in the genes were seen in four patients. Both cyclin D1 and D3 mRNA levels correlated positively with lymphocyte doubling time (LDT) and inversely with Rai stage and duration of disease. In addition, a significant correlation was observed between cyclin D mRNA levels and survival, with patients having high levels of cyclin D1, and to a lesser extent cyclin D3, mRNA having the best survival. Thus, cyclin D1 and D3 are relatively overexpressed in CLL cells and patients with higher levels have low stage disease, long LDT and prolonged survival. Further studies should evaluate the predictive value of cyclin D measurements in comparison to other prognostic markers in CLL.

Adult↗
PubMed2004

IMRT for postoperative treatment of gastric cancer: covering large target volumes in the upper abdomen: a comparison of a step-and-shoot and an arc therapy approach.

PURPOSE: Data from the randomized Intergroup Trial 116 suggest effectiveness of adjuvant radiochemotherapy in patients with advanced gastric cancer. Late toxicity, however, especially with respect to the kidneys, may pose significant longtime problems. Intensity-modulated radiotherapy (IMRT) may reduce toxicity to organs at risk. To evaluate the relative merits of different IMRT approaches, we performed a plan comparison between a step-and-shoot class solution and an AP-PA setup, a conventional box technique and the Peacock tomotherapy approach. METHODS AND MATERIALS: Computed tomographies and structure data from 15 patients who had been treated postoperatively for advanced (T3/T4/N+) gastric cancer at our department formed the basis of our plan comparison study. For each patient data set, 5 plans or plan combinations (conventional 3D plan, AP-PA plan, step-and-shoot IMRT, tomotherapy with 1-cm or 2-cm collimation) were chosen, and evaluation was performed for a total dose of 45 Gy delivered as the median dose to the target volume for each plan or plan combination. RESULTS: Median kidney dose generated from the IMRT plans is reduced individually by >50% for the kidney with the highest exposure (usually the left kidney) from 20 to 30 Gy with conventional 3D planning down to values between 8 and 10 Gy for IMRT. On average, median dose to the right kidney is the same for the conventional box technique and IMRT (between 8 and 10 Gy) but lower for the AP-PA technique. In 3 patients, kidney dose might have been ablative for both kidneys with both the AP-PA technique and the box technique, whereas it was acceptable with IMRT. Median dose to the liver was subcritical with all modalities but lowest with AP-PA fields. Differences between step-and-shoot IMRT and tomotherapy plans are small when compared to the differences between IMRT plans and conventional conformal 3D plans. For some patients, however, their body and target diameters obviate treatment with tomotherapy. Treatment time for the step-and-shoot approach and for tomotherapy with 2-cm collimation can be kept <20 min. CONCLUSIONS: For postoperative radiotherapy of advanced gastric cancer, step-and-shoot IMRT as well as tomotherapy can deliver efficient doses to target volumes while delivering dose to the kidneys in a fashion that is different from a conventional technique and is clearly advantageous in a small number of patients. An advantage for the majority of patients is likely with the normal tissue complication probability data presented in this series, but, given the uncertainty of the reaction of the kidney to inhomogeneous dose distributions, cannot be considered unequivocal at the moment. Different technical limitations apply to the different IMRT techniques. The choice of approach is therefore determined by departmental circumstances.

Humans↗
PubMed2004

The three-dimensional organization of telomeres in the nucleus of mammalian cells.

BACKGROUND: The observation of multiple genetic markers in situ by optical microscopy and their relevance to the study of three-dimensional (3D) chromosomal organization in the nucleus have been greatly developed in the last decade. These methods are important in cancer research because cancer is characterized by multiple alterations that affect the modulation of gene expression and the stability of the genome. It is, therefore, essential to analyze the 3D genome organization of the interphase nucleus in both normal and cancer cells. RESULTS: We describe a novel approach to study the distribution of all telomeres inside the nucleus of mammalian cells throughout the cell cycle. It is based on 3D telomere fluorescence in situ hybridization followed by quantitative analysis that determines the telomeres' distribution in the nucleus throughout the cell cycle. This method enables us to determine, for the first time, that telomere organization is cell-cycle dependent, with assembly of telomeres into a telomeric disk in the G2 phase. In tumor cells, the 3D telomere organization is distorted and aggregates are formed. CONCLUSIONS: The results emphasize a non-random and dynamic 3D nuclear telomeric organization and its importance to genomic stability. Based on our findings, it appears possible to examine telomeric aggregates suggestive of genomic instability in individual interphase nuclei and tissues without the need to examine metaphases. Such new avenues of monitoring genomic instability could potentially impact on cancer biology, genetics, diagnostic innovations and surveillance of treatment response in medicine.

Animals↗
PubMed2004

Rearrangements of the telomeric region of mouse chromosome 11 in Pre-B ABL/MYC cells revealed by mBANDing, spectral karyotyping, and fluorescence in-situ hybridization with a subtelomeric probe.

Previous work has demonstrated that chromosome 11 is trisomic or shows a duplicated region encompassing the E1/E2 band of chromosome 11 in 90% of v-abl/myc-induced plasmacytomas (Wiener et al. 1995). In the present report, we have studied BALB/c PreB lymphocytes that were immortalized by v-abl and stably transfected with a conditional MycER vector (Mai et al. 1999). These cells, termed PreB ABL/MYC, showed changes in the E1/E2 bands of chromosome 11 that are similar to those reported previously for v-abl/myc-induced plasmacytomas. This was shown by the use of chromosome painting, SKY, FISH and mBAND. Our findings suggest that the Pre-B ABL/MYC cells may be used to analyse the genetic changes affecting chromosome 11 that are associated with v-abl/myc-dependent tumorigenesis in mouse B cells.

Animals↗
PubMed2004

Cell cycle-dependent 3D distribution of telomeres and telomere repeat-binding factor 2 (TRF2) in HaCaT and HaCaT-myc cells.

Telomeres are specialized structures at the ends of the chromosomes that, with the help of proteins--such as the telomere repeat-binding factor TRF2 -, form protective caps which are essential for chromosomal integrity. Investigating the structure and three-dimensional (3D) distribution of the telomeres and TRF2 in the nucleus, we now show that the telomeres of the immortal HaCaT keratinocytes are distributed in distinct non-overlapping territories within the inner third of the nuclear space in interphase cells, while they extend more widely during mitosis. TRF2 is present at the telomeres at all cell cycle phases. During mitosis additional TRF2 protein concentrates all around the chromosomes. This change in staining pattern correlates with a significant increase in TRF2 protein at the S/G2 transition as seen in Western blots of synchronized cells and is paralleled by a cell cycle-dependent regulation of TRF2 mRNA, arguing for a specific role of TRF2 during mitosis. The distinct territorial localization of telomeres is abrogated in a HaCaT variant that constitutively expresses c-Myc--a protein known to contribute to genomic instability. These cells are characterized by overlapping telomere territories, telomeric aggregates (TAs), that are accompanied by an overall irregular telomere distribution and a reduced level in TRF2 protein. These TAs which are readily detectable in interphase nuclei, are similarly present in mitotic cells, including cells in telophase. Thus, we propose that TAs, which subsequently also cluster their respective chromosomes, contribute to genomic instability by forcing an abnormal chromosome segregation during mitosis.

Cell Cycle↗
PubMed2003

Metaphase FISHing of transgenic mice recommended: FISH and SKY define BAC-mediated balanced translocation.

The evolving trend to use larger transgenes and their associated increased chance of unexpected genetic events mandates more careful characterization of transgenic mice. In characterizing our five new mouse strains transgenic for the BAC, bEMS4, we have identified the highest copy number reported to date: the stable incorporation of approximately 40 copies of a 194-kb expressed transgene in a single insertion site. We caution, however, that standard molecular techniques failed to identify a balanced translocation in another strain, and an inappropriate site of insertion in a third. Molecular cytogenetic analysis using metaphase FISH was the minimum level of characterization needed to reveal these unexpected genetic events. In addition, we combined FISH and SKY to identify the transgene at the breakpoints of the balanced translocation, t(3;9). This is the first description of a BAC-mediated chromosomal rearrangement and the first application of SKY to identify transgene-induced chromosomal rearrangements.

Animals↗
PubMed2003

Optimization of dose distributions for adjuvant locoregional radiotherapy of gastric cancer by IMRT.

BACKGROUND AND PURPOSE: Locoregional relapse is a problem frequently encountered with advanced gastric cancer. Data from the randomized Intergroup trial 116 suggest effectiveness of adjuvant radiochemotherapy, albeit with significant toxicity. The potential of intensity-modulated radiotherapy (IMRT) to reduce toxicity by significantly reducing maximum and median doses to organs at risk while still applying sufficient dose to the target volume in the upper abdomen was studied. PATIENT AND METHODS: For a typical configuration of target volumes and organs, a step-and-shoot IMRT plan (eight beam orientations), developed as a class solution for treatment of tumors in the upper abdomen (Figures 1 to 3), a conventional plan, a combination of the conventional plan with a kidney-sparing boost plan, and a conventional plan with noncoplanar ap and pa fields for improved kidney sparing were compared with respect to coverage of target volume and dose to organs at risk with a dose of 45 Gy delivered as the median dose to the target volume. RESULTS: When using the conventional three-dimensionally planned box techniques, the right kidney could be kept below tolerance, but median dose to the left kidney amounted to between 14.8 and 26.9 Gy, depending on the plan. IMRT reduced the median dose to the left kidney to 10.5 Gy, while still keeping the dose to the right kidney < 8 Gy. Liver was spared better with IMRT. Dose to the lungs was not significantly different, and dose to the spinal cord was higher (but well below tolerance) with IMRT. The dose distribution within the target volume was less homogeneous than for the conventional plans. With regard to target coverage, > 90% of prescription dose were delivered to > 90% of target volume with IMRT (Table 1). CONCLUSION: IMRT has the potential to deliver efficient doses to target volumes in the upper abdomen, while delivering dose to organs at risk in a more advantageous fashion than a conventional technique. For clinical implementation, the possibility of extensive organ motion in the upper abdomen has to be taken into account for treatment planning and patient positioning. The multitude of potential risks related to its application has to be the subject of thorough follow-up and further studies.

Adenocarcinoma↗