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Biomedical subjects

Z Fuks

Publications and source records attributed to Z Fuks.

At least 73 records · Page 4Linked to original sources
PubMed1996

Severed corticospinal axons recover electrophysiologic control of muscle activity after x-ray therapy in lesioned adult spinal cord.

Mechanical injury to the adult mammalian spinal cord results in permanent loss of structural integrity at the lesion site and of the brain-controlled function distal to the lesion. Some of these consequences were permanently averted by altering the cellular constituents at the lesion site with x-irradiation delivered within a critical time window after injury. We have reported in a separate article that x-irradiation of sectioned adult rat spinal cord resulted in restitution of structural continuity and regrowth of severed corticospinal axons across and deep into the distal stump. Here, we report that after x-ray therapy of the lesion site severed corticospinal axons of transected adult rat spinal cord recover electrophysiologic control of activity of hindlimb muscles innervated by motoneurons distal to the lesion. The degree of recovery of control of muscle activity was directly related to the degree of restitution of structural integrity. This restitution of electrophysiologic function implies that the regenerating corticospinal axons reestablish connectivity with neurons within the target field in the distal stump. Our data suggest that recovery of structural continuity is a sufficient condition for the axotomized corticospinal neurons to regain some of their disrupted function in cord regions distal to the lesion site.

Animals↗
PubMed1996

Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis.

Stress is believed to activate sphingomyelinase to generate ceramide, which serves as a second messenger in initiating the apoptotic response. Conclusive evidence for this paradigm, however, is lacking. In the present study, we used a genetic approach to address this issue directly. We show that lymphoblasts from Niemann-Pick patients, which have an inherited deficiency of acid sphingomyelinase activity, fail to respond to ionizing radiation with ceramide generation and apoptosis. These abnormalities are reversible up on restoration of acid sphingomyelinase activity by retroviral transfer of human acid sphingomyelinase cDNA. Acid sphingomyelinase knockout mice also expressed defects in radiation-induced ceramide generation and apoptosis in vivo. Comparison with p53 knockout mice revealed that acid sphingomyelinase-mediated apoptosis and p53-mediated apoptosis are likely distinct and independent. These genetic models provide definitive evidence for the involvement of acid sphingomyelinase in one form of stress-induced apoptosis.

Animals↗
PubMed1996

Conformal radiation treatment of prostate cancer using inversely-planned intensity-modulated photon beams produced with dynamic multileaf collimation.

PURPOSE: To implement radiotherapy with intensity-modulated beams, based on the inverse method of treatment design and using a multileaf collimation system operating in the dynamic mode. METHODS AND MATERIALS: An algorithm, based on the inverse technique, has been integrated into the radiotherapy treatment-planning computer system in our Center. This method of computer-assisted treatment design was used to derive intensity-modulated beams to optimize the boost portion of the treatment plan for a patient with a T1c cancer of the prostate. A dose of 72 Gy (in 40 fractions) was given with a six-field plan, and an additional 9 Gy (in five fractions) with six intensity-modulated beams. The intensity-modulated fields were delivered using dynamic multileaf collimation, that is, individual leaves were in motion during radiation delivery, with the treatment machine operating in the clinical mode. Exhaustive quality assurance measurement and monitoring were carried out to ensure safe and accurate implementation. RESULTS: Dose distribution and dose-volume histogram of the "inverse method" boost plan and of the composite (72 Gy primary + 9 Gy boost) plan were judged clinically acceptable. Compared to a manually designed boost plan, the inverse treatment design gave improved conformality and increased dose homogeneity in the planning target volume. Film and ion chamber dosimetry, performed prior to the first treatment, indicated that each of the six intensity-modulated fields was accurately produced. Thermoluminescent dosimeter (TLD) measurements performed on the patient confirmed that the intended dose was delivered in the treatment. In addition, computer-aided treatment-monitoring programs assured that the multileaf collimator (MLC) position file was executed to the specified precision. In terms of the overall radiation treatment process, there will likely be labor savings in the planning and the treatment phases. CONCLUSIONS: We have placed into clinical use an integrated system of conformal radiation treatment that incorporated the inverse method of treatment design and the use of dynamic multileaf collimation to deliver intensity-modulated beams. The system can provide better treatment design, which can be implemented reliably and safely. We are hopeful that improved treatment efficacy will result.

Humans↗
PubMed1996

A method of incorporating organ motion uncertainties into three-dimensional conformal treatment plans.

PURPOSE: We describe a method of incorporating organ motion into three-dimensional (3D) conformal treatment plans, which predicts the effect of organ motion on the calculated dose to both the clinical target volume (CTV) and nontarget organs. METHODS AND MATERIALS: The method is based on measurements of organ motion by means of multiple computed tomography (CT) scans from a group of "reference" patients, in which the data consist of previously drawn contours of the target and nontarget organs. A computer program records the differences in contour position and shape that occur between scans in the reference data, and according to those differences adjusts the contours and dose calculation points of a "study" patient currently being planned, thus simulating organ motion. Dose-volume histograms (DVHs) are accumulated, and the process is repeated over the set of reference patient scans, resulting in a set of treatment plans that are ranked according to a dose-based endpoint. Two plans are selected corresponding to specified lower and upper confidence limits in the endpoint, and the DVHs from these plans are displayed for comparison with the DVHs from the nominal plan in the absence of motion. RESULTS: As an example of the method's use, it is applied to a 6-field conformal treatment plan for prostate cancer. Confidence limit DVHs of the CTV and rectal wall (in which the plans were ranked by probabilities for tumor control and normal tissue complication, respectively) are presented and compared to those from the nominal plan. CONCLUSION: The method provides a means of estimating the uncertainty in dose delivered by a treatment plan when organ motion is present. It is generally applicable to any treatment site for which data in the form of multiple CT scans are available, and can be extended to include other treatment uncertainties such as variation in patient positioning.

Humans↗
PubMed1996

Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.

The induction of programmed cell death, or apoptosis, involves activation of a signalling system, many elements of which remain unknown. The sphingomyelin pathway, initiated by hydrolysis of the phospholipid sphingomyelin in the cell membrane to generate the second messenger ceramide, is thought to mediate apoptosis in response to tumour-necrosis factor (TNF)-alpha, to Fas ligand and to X-rays. It is not known whether it plays a role in the stimulation of other forms of stress-induced apoptosis. Given that environmental stresses also stimulate a stress-activated protein kinase (SAPK/JNK), the sphingomyelin and SAPK/JNK signalling systems may be coordinated in induction of apoptosis. Here we report that ceramide initiates apoptosis through the SAPK cascade and provide evidence for a signalling mechanism that integrates cytokine- and stress-activated apoptosis.

Animals↗
PubMed1996

Modulation of the Apoptotic Response: Potential for Improving the Outcome in Clinical Radiotherapy.

The most prevalent mechanism of cell kill by radiation is mitosis dependent and results from lethal DNA double-strand breaks and failure to maintain normal replication. Apoptosis is believed to represent a minor component of the clinical effects of radiation. Apoptosis is a preprogrammed death pathway that is constitutively expressed in many cells, albeit in an inactive form, regulated by antiapoptotic mechanisms. Data are presented to show that in irradiated cells the balance between proapoptotic and antiapoptotic signaling may determine the apoptotic outcome in vitro and in vivo. This balance can be modulated by pharmacological intervention to produce a more proapoptotic phenotype, increasing apoptotic cell kill by radiation. These studies establish the basic principles of signaling-based apoptosis therapy, designed to overcome the relative resistance to radiation-induced apoptosis and to improve the therapeutic ratio in the treatment of human tumors with fractionated radiation.

Journal Article↗
PubMed1995

Three dimensional conformal treatment planning with multileaf collimators.

PURPOSE: Three dimensional conformal radiation treatments are complex, often involving large numbers of blocked or multileaf collimated fields that shape regions of high dose to conform to the treatment volume. As manual definition and digitization of aperture shapes and their corresponding multileaf configurations can be impractically time consuming, it was necessary to integrate the planning of multileaf fields into an existing three dimensional treatment planning system and improve the efficiency of treatment delivery to make these treatments feasible on a routine basis. METHODS AND MATERIALS: A subfunction of the Beam's Eye View (BEV) component can be used to automatically generate a continuous aperture shape with a margin around the tumor to account for beam penumbra, and excluding any normal structures to be spared (each with its own margin). To convert a continuous aperture shape into one defined by the multileaf collimator (MLC), a leaf coverage mode is chosen to determine how leaves are fitted to aperture shapes. The conversion process also considers parameters of the specific MLC system, e.g., leaf thickness and the number of leaves. If normal structures to be shielded split the target into multiple regions, more than one multileaf aperture can result. An interactive leaf adjustment routine is also provided to allow for modification of individual leaf positions. Dose calculation programs then take into account multileaf apertures for computation of dose distributions using a pencil beam convolution model. Finally, prescription files specifying leaf and jaw configurations are prepared in treatment machine specific formats and downloaded to the computers driving the multileaf collimators and other components of the treatment machines. RESULTS AND CONCLUSION: An example is presented of a prostate treatment plan, with MLC configurations, dose distributions, and treatment delivery description, along with discussion of clinical implementation at Memorial Hospital.

Adenocarcinoma↗
PubMed1995

Potentiation of apoptosis by treatment with the protein kinase C-specific inhibitor safingol in mitomycin C-treated gastric cancer cells.

BACKGROUND: Protein kinase C (PKC) is a family of enzymes that function in processes relevant to carcinogenesis, tumor cell metastasis, and apoptosis. Safingol, an optical isomer (the L-threo enantiomer) of dihydrosphingosine, is a specific inhibitor of PKC and might represent a novel agent for anticancer therapy. Preclinical animal studies show that safingol alone has a minimal effect on tumor cell growth, but combining this compound with conventional chemotherapy agents dramatically potentiates their antitumor effects. It has been suggested that many chemotherapeutic agents exert their antitumor effects by inducing apoptosis. PURPOSE: We wanted to determine the extent to which safingol, alone or in combination with a standard chemotherapeutic agent (mitomycin C [MMC]), would promote apoptosis in gastric cancer cells in vitro. Furthermore, we investigated whether the induction of apoptosis in the treated cells was affected by their p53 tumor suppressor status or their drug-resistance status. METHODS: SK-GT-5 (p53-deficient and MMC-resistant) and MKN-74 (p53 wild-type and MMC-sensitive) gastric cancer cells were exposed to either no drug, safingol (50 microM) alone, MMC (5 micrograms/mL) alone, or a combination of safingol (50 microM) and MMC (5 micrograms/mL). In some experiments, cells were exposed simultaneously to safingol and the PKC activator, 3-phorbol 12-myristate 13-acetate (PMA), prior to treatment with MMC. Apoptosis was measured by two methods: 1) quantitative fluorescence microscopy of nuclear chromatin condensation in cells stained with the dye, bisbenzamide trihydrochloride (Hoechst-33258), and 2) terminal deoxynucleotidyl transferase (TdT) labeling of the 3'-OH ends of DNA fragments produced in apoptotic cells. RESULTS: As determined by quantitative fluorescence microscopy, exposure of SK-GT-5 cells to safingol alone induced apoptosis in 2% +/- 1% (mean +/- SD) of the cells, and MMC alone increased that level to 18% +/- 1%. However, the combination of safingol and MMC induced apoptosis in 39% +/- 1% of the cells (P < .001, for the drug combination versus MMC alone). With MKN-74 cells, safingol alone induced apoptosis in 8% +/- 3% of the cells, whereas MMC alone induced apoptosis in 40% +/- 4% of treated cells and the combination of safingol and MMC induced apoptosis in 83% +/- 4% of the cells. Similar results were obtained with the TdT assay. Simultaneous exposure of cells to safingol and PMA abrogated the safingol-mediated enhancement of MMC-induced apoptosis. CONCLUSIONS: The PKC inhibitor safingol enhances the cytotoxic effect of the chemotherapeutic agent MMC in gastric cancer cells by promoting drug-induced apoptosis. The induction of apoptosis occurs regardless of the p53 status or the drug-resistance status of the cells.

Apoptosis↗
PubMed1995

Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals.

The sphingomyelin pathway, which is initiated by sphingomyelin hydrolysis to generate the second messenger ceramide, signals apoptosis for tumor necrosis factor alpha, Fas, and ionizing radiation. In the present studies, the anticancer drug daunorubicin also stimulated ceramide elevation and apoptosis in P388 and U937 cells. Cell-permeable analogs of ceramide, but not other lipid second messengers, mimicked daunorubicin in inducing apoptosis. Daunorubicin-stimulated ceramide elevation, however, did not result from sphingomyelin hydrolysis, but rather from de novo synthesis via activation of the enzyme ceramide synthase. An obligatory role for ceramide synthase was defined, since its natural specific inhibitor, fumonisin B1, blocked daunorubicin-induced ceramide elevation and apoptosis. These studies demonstrate that ceramide synthase activity can be regulated in eukaryotes and constitute definitive evidence for a requirement for ceramide elevation in the induction of apoptosis.

Amidohydrolases↗
PubMed1995

Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide.

Recent studies have proposed that tumor necrosis factor alpha (TNF-alpha) and ionizing radiation induce apoptosis by activating hydrolysis of sphingomyelin to ceramide. Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis. Herein, we report that internucleosomal DNA fragmentation, characteristic of apoptosis and induced by ionizing radiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X mRNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA fragmentation after exposure to TNF-alpha and C2-ceramide was also associated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, while Bcl-X mRNA production was unaffected. These results suggest that modulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-alpha. Changes in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF-alpha in some human and tumor cells.

Apoptosis↗
PubMed1995

Optimization of intensity-modulated 3D conformal treatment plans based on biological indices.

To overcome the limitations of the intensity modulation optimization techniques based on dose criteria, we introduce a method for optimizing intensity distributions in which we employ an objective function based on biological indices. The objective function also includes constraints on dose and dose-volume combinations to ensure that the results are consistent with the physician's judgement. We apply a variant of the steepest-descent method to optimize the objective function. The method is three-dimensional and incorporates scattered radiation in the optimization process using an iterative scheme employing the pencil beam convolution method. Previously we had shown that the inverse technique of obtaining optimum intensity distributions, for which the objectives are defined in terms of a desired uniform dose to the target volume and desired upper limits of dose to normal organs, produces satisfactory approximations of the desired dose distributions for prostate plans. However, for lung, the performance of this technique was considerably inferior. Our conclusion was that, in general, it is not sufficient to specify the objectives of optimization purely in terms of a desired pattern of dose and that the objectives should also incorporate biology, perhaps in the form of biological indices. We demonstrate that the biology-based approach produces lung plans that are superior to those produced when only dose-based objectives are used. For the treatment of prostate, the two methods produce comparable dose distributions.

Adenocarcinoma↗
PubMed1995

Conformal radiation treatment: a critical appraisal.

Significant technical advances have improved the precision of radiation treatment of human malignancies and permitted dose-escalation studies. However, a number of challenges remain, particularly in the clinical and radiobiological aspects of radiotherapy. Even with these deficiencies, it is likely that improved overall treatment results will be forthcoming with 3DCRT. Nevertheless, the cost-effectiveness of this approach needs to be assessed, based on the magnitude of the improvement in the treatment of various disease sites.

Clinical Trials as Topic↗
PubMed1995

Beam characteristics of a new generation 50 MeV racetrack microtron.

The first of a new generation of microtron accelerators has been installed and tested. It is currently in use for multisegment conformal radiotherapy at our institution. The unit produces x rays and electrons from 10 to 50 MeV in 5 MeV increments. It incorporates a 64 leaf, doubly focused multileaf collimator (MLC), which can be used to shape x-ray and electron beams. Both x-ray and electron beams are produced by magnetically scanning the electron beams from the accelerator. The new generation unit incorporates a purging magnet to sweep away any primary or secondary electrons that pass through the target(s). In this paper, the beam characteristics of the accelerator that were studied during acceptance testing are described. Representative examples of depth doses, beam profiles, output factors, and elementary beam distributions are presented and discussed, in comparison with the earlier generation of microtron accelerators and with other radiotherapy machines.

Humans↗
PubMed1995

Significance of normal serum prostate-specific antigen in the follow-up period after definitive radiation therapy for prostatic cancer.

PURPOSE: To determine the prognostic significance of a normal serum prostate-specific antigen (PSA) level in patients with prostatic cancer with long-term follow-up evaluation after radiotherapy. MATERIALS AND METHODS: PSA information was available in 403 patients (38%) who were treated with pelvic lymph node dissection and retropubic radioactive iodine-125 implantation. One hundred eighty-two patients had a normal serum PSA level (< or = 4.0 ng/mL) the first time this test was conducted during the follow-up period, designated PSA-1. RESULTS: Among patients with PSA-1 values < or = 1.0 ng/mL, the 5-year PSA relapse-free survival rate was 85% compared with 27%, respectively, among those with PSA values in the higher range of normal (P < .00001). Multivariate analysis demonstrated that only a PSA-1 value greater than 1.0 to < or 4.0 (P < .00001) and grade II/III histology (P = .009) had a negative impact on continued PSA relapse-free survival. The only independent variable identified by a multivariate analysis to affect local relapse-free survival (LRFS) was a PSA-1 value greater than 1.0 to < or = 4.0 ng/mL (P < .004), while high-grade histology (P < .0001) and local failure (P < .001) were the only significant variables to affect distant metastases-free survival (DMFS). CONCLUSION: Patients with PSA values < or = 1.0 ng/mL are significantly less likely to have a subsequent relapse after therapy than those with levels greater than 1.0 to < or = 4.0 ng/mL. Continuously maintained PSA levels of < or = 1.0 ng/mL after treatment may serve as an end point for early evaluation of the efficacy of experimental radiotherapy protocols in prostate cancer.

Adenocarcinoma↗