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Biomedical subjects

I Rosenberg

Publications and source records attributed to I Rosenberg.

At least 19 recordsLinked to original sources
PubMed1992

Phosphorylation of 9-(2-phosphonomethoxyethyl)adenine and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine by AMP(dAMP) kinase from L1210 cells.

Acyclic nucleotide analogues 9-(2-phosphonomethoxyethyl)adenine (PMEA) and 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine ((S)-HPMPA) which display potent antiviral activity are transformed in the cells to their mono- and disphosphoryl derivatives. We purified from mouse L1210 cells the enzyme that in two steps phosphorylates PMEA and (S)-HPMPA to their diphosphoryl derivatives and found that it co-purifies with AMP(dAMP) kinase activity; the best substrates of this enzyme were AMP, ADP and dAMP. Other nucleoside 5'-triphosphates or creatine phosphate could not be substituted for ATP as a phosphate donor. Our results also indicated that at least one other enzyme (creatine kinase) is capable of transforming the monophosphoryl derivatives of the studied compounds to their respective diphosphates.

Adenine↗
PubMed1992

Transformation by human papillomavirus type 16 (HPV16) DNA but not HPV6b DNA is enhanced by addition of the human cytomegalovirus enhancer.

Primary human cervical epithelial cells immortalized by human papillomavirus type 16 (HPV16) DNA exhibit altered morphology and differentiation characteristic of transformation, but show a lack of transformed phenotype relative to HPV18 DNA immortalized cells in terms of anchorage-independent growth (Pecoraro, Lee, Morgan, and Defendi, 1991, Am. J. Pathol. 138, 1-8). This is completely corrected by inserting a strong heterologous enhancer derived from human cytomegalovirus DNA upstream from the HPV16 long control region. The cells immortalized by this DNA form colonies in agar comparable to those formed by HPV18 DNA immortalized cells. The enhanced transformation capability correlates with increased levels of HPV16 E6-E7 and E5 transcripts. The HPV16 DNA containing this strong enhancer also transforms C127 mouse cells with increased efficiency and strength relative to the natural HPV16 DNA, as measured by the numbers and size of the colonies in agar. The positive effects of this strong enhancer appear specific for HPVs associated with genital malignancies such as HPV16, since HPV6b DNA (primarily in benign tumors) with or without the strong cytomegalovirus enhancer is incapable of immortalizing primary human cervical epithelial cells or allowing efficient growth of C127 mouse cells in agar. These results suggest that the diminished oncogenic properties of HPV16 versus HPV18 DNA in cultured cells and in human malignancies may reside in the long control regions of these viruses and, additionally, may define another difference in the oncogenic properties of HPVs associated with benign or malignant genital neoplasia.

Animals↗
PubMed1992

Quantification of doses to mediastinal lymph nodes in Hodgkin's disease.

Hodgkin's disease is highly curable today. Radiotherapy (RT) is the treatment of choice in the early stages. A mantle field is often used in the RT of Hodgkin's disease, and the technique and dosimetry are quite complex. We used computerized tomography (CT)-based dosimetry to determine doses delivered to different mediastinal nodes with the commonly used technique in Hodgkin's disease that was originally described by Kaplan. We used dose-volume histograms to determine doses to various groups of nodes in nine patients. Significant inhomogeneity (30%, 30%, 35%, 35%, 30%, 40%, 35%, 35%, and 30% in the nine patients) in dose distribution was found within the mediastinum. With the advent of 3-dimensional CT-based treatment planning, we are able to quantify such inhomogeneities. The question arises whether a homogeneous, lesser dose can achieve equal results. Average doses and "effective doses" were also calculated. The "effective doses" in eight patients (for a prescribed dose of 44 Gy) with a midline posterior spinal cord block added at 20 Gy were 37.3 Gy, 34.3 Gy, 36.0 Gy, 38.4 Gy, 35.8 Gy, 38.1 Gy, 36.7 Gy, and 36.7 Gy, respectively. A homogeneous dose equivalent to effective dose may achieve the same control as an inhomogeneous dose delivery. Prospective 3-D dosimetric studies are required to confirm this concept.

Hodgkin Disease↗
PubMed1992

Beam's eye view--based radiation therapy: description of methods.

Improving three-dimensional target definitions and dose delivery may improve local control rates in radiation therapy. Computed tomography (CT)-based treatment planning is one step toward achieving this goal, but further progress is possible with beam's eye view (BEV)-based planning. Initially, CT is performed with the patient in the treatment position, and data are transferred to a computerized treatment planning system. Target volumes and vital structures are outlined on CT sections and digitized, and a treatment plan is produced. BEV display is used to calculate the angles needed for oblique fields that would avoid irradiation of vital structures. A BEV printout is obtained along with simulation radiographs. The radiograph is overlaid on the printout, all identified structures are matched, and the target volumes are transferred from the printout to the radiograph. BEV-based planning can improve three-dimensional coverage of a tumor, irradiation techniques, and the therapeutic ratio by decreasing the irradiation of normal tissue. The extra time required for BEV planning is acceptable, but further studies of long-term outcomes and cost-benefit analyses are needed.

Humans↗
PubMed1992

[Color-Doppler echography of the testis. Study technique and vascular anatomy].

Color-Doppler sonography has recently made it possible to image scrotal vascularity non-invasively. This study was undertaken to determine the normal color-Doppler appearance and distribution of scrotal vessels and to define the technical principles of the examination. Color-Doppler imaging was effective in detecting both funicolar and testicular vessels. Among these, capsular (25/25), trans-testicular (10/25), centripetal and recurrent (25/25) arteries were easily identified. Waveforms analysis allowed to differentiate veins from arteries within testis and to distinguish (8/10) supratesticular (high impedance pattern with absent diastolic flow) from intratesticular arteries (low impedance pattern with high levels of diastolic flow). The optimal color depiction of scrotal vascularity needed the appropriate selection of several imaging parameters to increase detection of low-velocity, low-volume flows within the small testicular vessels. Such parameters included: PRF (ranging 1500 to 600 Hz), wall filters (ranging 25 to 50 Hz), color gain (maximized for optimal sensitivity while avoiding excessive color noise), color vs. echo priority (ranging 70 to 90%) and color persistence (adjusted to high values). In conclusion, color-Doppler imaging is capable of reliably showing the normal anatomy of testicular vessels. It could make a reliable substitute for scintigraphy and continuous wave Doppler in diagnosing scrotal conditions that alter blood flow.

Adult↗
PubMed1991

Mac-2-binding glycoproteins. Putative ligands for a cytosolic beta-galactoside lectin.

Mac-2, a galactose-binding lectin secretion by activated macrophages, is the major non-integrin laminin-binding protein in these cells. Mac-2 is also expressed by epithelial cells in the intestine and kidney. We wished to identify intestinal glycoproteins other than laminin that have a high affinity for Mac-2 and that could be considered as candidate ligands or partners for this lectin in intestinal epithelium. Certain lines of human colon adenocarcinoma cells produce two Mac-2-binding glycoproteins (M2BP-1 and M2BP-2) that were identified by their avid association with Mac-2 following detergent lysis and immunoprecipitation. These glycoproteins do not share a common epitope with Mac-2, and the interaction between Mac-2 and these proteins is mediated through the carbohydrate-binding domain of Mac-2 and sugar moieties on M2BP-1 and M2BP-2. M2BP-1 (98 kDa) and M2BP-2 (70 kDa) were purified by immunoaffinity chromatography and were specifically eluted with either galactose or lactose. Peptide maps revealed that M2BP-1 and M2BP-2 are structurally related. M2BP-1 is secreted and could conceivably associate with Mac-2 extracellularly. N-terminal sequence analysis of M2BP-2 suggests that these glycoproteins represent a unique subset of candidate ligands for this mammalian beta-galactoside lectin.

Adenocarcinoma↗
PubMed1991

Beams eye view-based photon radiotherapy I.

Geographic miss, dosimetric miss (underdosing), and proximity of the tumor to sensitive normal tissues are some of the causes of inadequate radiation dose delivery; this is one of many causes of failure after radiotherapy. In the past decade, computerized tomography (CT)-based treatment planning has helped to overcome some of these problems. Beam's eye view (BEV)-based radiotherapy planning is an improvement over CT-based treatment planning that may further increase the therapeutic ratio. Since January 1988, we have treated 198 patients with BEV-based photon radiotherapy. About 40% of our patients treated with radical radiotherapy undergo BEV-based treatment, and about 70% of patients who undergo planning CT in the treatment position receive BEV-based radiotherapy. Our findings are as follows: (a) routine use of BEV-based RT (BEVRT) is possible in a busy radiation oncology department; (b) BEVRT improves geometric coverage of tumors; (c) BEVRT is extremely useful in the design of oblique portals; (d) time commitments for various members of the RT treatment-planning team are reasonable; (e) BEVRT helps individualize RT technique; (f) preliminary data suggest decreased acute toxicity with the use of BEVRT for prostate cancer patients. Whether these advantages will help to improve the outcome (i.e., improve local control and survival) and/or decrease the long-term toxicity is not yet known.

Breast Neoplasms↗
PubMed1991

Optimization of radical radiotherapy with beam's eye view techniques for non-small cell lung cancer.

The presence of vital and sensitive organs such as the spinal cord, heart, and lungs makes curative radiotherapy of non-small cell lung cancer difficult to implement and necessitates use of oblique portals. Defining the target volumes in oblique portals is very difficult. We now show, for non-small cell lung cancer, how beam's eye view-based radiotherapy can be used for accurate delineation of treatment volumes and for avoidance of real or dosimetric geographic misses. Furthermore, the beam's eye view-based method enables one to project accurately a 2-dimensional image of 3-dimensional disease extension, especially in oblique fields, thus facilitating the design of accurate customized blocking and avoiding inadvertent blocking of the tumor or unnecessary irradiation of normal tissues. Beam's eye view volumetric analysis is helpful for devising a customized treatment plan for each patient. Such customization may minimize local failure, which is one cause of poor results of radiotherapy in this site. Beam's eye view-based radiotherapy has the potential of improving local control and hence may improve the survival of patients with non-small-cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗
PubMed1991

An anterior appositional electron field technique with a hanging lens block in orbital radiotherapy: a dosimetric study.

A technique for orbital radiotherapy is presented consisting of an anterior, appositional electron beam with a hanging lens block. The beam was modified by introducing two 1.6 mm thick plastic spoilers, at about 3 cm and 15 cm from the lens, to boost in-scattering of electrons under the block. The 9 mm diameter, 2 cm long stainless steel cylindrical block was suspended 0.5-1.0 cm above the eye. We performed film, TLD (Thermo Luminescent Dosimetry), and diode dosimetry to determine the dose fill-in behind the lens. The introduction of the spoilers dramatically changed the dose distribution. The maximum dose under the block increased from 66% to 85% of the open field dose. Moreover, the dose to the posterior surface of the globe directly underneath the block, at a depth of 3 cm, increased from 48% to 76% of maximum dose, while the dose to the lens was still below 20%. This is a simple and easily reproducible treatment and is an improvement on a previously described technique. The dose distribution is adequate for cases where the target volume surrounds and is posterior to the globe.

Electrons↗
PubMed1991

The use of a negative beam to simulate a midline block.

The physics behind the use of a negatively weighted beam to calculate the dose distribution under a midline block in computerized treatment planning systems is reviewed. To correctly reproduce the dose under the block, it is necessary and sufficient to know the relative dose at one reference depth on the central axis under the block. If the relative weight of the negative beam is then adjusted to produce agreement at that depth, good agreement can be obtained throughout. Comparisons between calculated and measured dose distributions under a midline block are presented for two therapy beams with 4MV and 6MV nominal energies.

Computer Simulation↗
PubMed1991

Estimation of doses to heart, coronary arteries, and spinal cord in mediastinal irradiation for Hodgkin's disease.

Early-stage Hodgkin's disease is highly curable with radiotherapy. However, radiotherapy for Hodgkin's disease is not without complications, particularly those related to irradiation of the mediastinum. In attempts to decrease complications, it is important not to compromise the results. To plan such a strategy, one needs to know the doses delivered to various volumes of normal tissues with present techniques. However, such dose-volume data do not exist. Here we demonstrate, with computerized tomography-based dosimetric techniques, such a dose-volume relationship for the heart, coronary arteries, and spinal cord. The doses were determined retrospectively in eight patients. With a prescribed dose of 44 Gy, the volumes of the heart receiving at least 22, 26, 31, 35, 40, or 44 Gy were: 77%, 75%, 70%, 57%, 33%, and 2%, respectively. The average modal doses to the coronary arteries were: anterior interventricular artery, 18.48 Gy; circumflex arterial branch, 37.84 Gy; left coronary artery, 34.76 Gy; and right coronary artery, 36.96 Gy. The average maximum spinal cord dose was 37.25 Gy. A similar prospective documentation of dose-volume relationships and correlation with (functional) long-term complications may be helpful in the development of new strategies for decreasing complications.

Coronary Vessels↗
PubMed1991

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys.

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the in vitro replication of a number of retroviruses, including HIV-1 and HIV-2, simian immunodeficiency virus (SIV), simian AIDS-related virus (SRV), feline immunodeficiency virus (FIV) and Moloney murine sarcoma virus (MSV). PMEA causes a dose-dependent suppression of the induction of anti-SIVmacgp120 antibodies in SIV mac-infected rhesus monkeys. Complete suppression of anti-SIVmacgp120 antibodies was achieved in SIV-infected animals treated with PMEA at 2 x 10 or 2 x 5 mg/kg per day for 29 days. No toxic side-effects were noted during this treatment period. Antibodies against SIVmac gp120 appeared 1-2 weeks after PMEA treatment was stopped, but the antibody titre reached in these animals was significantly lower than in the SIVmac-infected animals who had not been treated with PMEA. Our data strongly suggest that PMEA should be pursued for its potential in the treatment of AIDS and other retrovirus infections.

Adenine↗
PubMed1990

Inhibition of avian myeloblastosis virus reverse transcriptase by diphosphates of acyclic phosphonylmethyl nucleotide analogues.

Diphosphates of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases were studied in the endogenous oligo(dT)12-18 primed reaction of reverse transcriptase from detergent-disrupted AMV(MAV) retrovirions. These diphosphates (analogues of nucleotide 5'-triphosphates) exhibited an inhibitory activity towards reverse transcriptase. This inhibitory activity was dependent on the character of the heterocyclic base and decreased in the order: 2-aminoadenine greater than adenine greater than guanine much greater than cytosine much greater than thymine greater than uracil. The 2-aminoadenine derivative was more potent than either AZT-TP or ddTTP, while PMEApp had approximately the same potency as the two reference compounds (IC50 approximately 1 microM at 20 microM competing substrate). This finding is consistent with the antiviral activity of the parent nucleotide analogues against retroviruses (including HIV).

Adenine↗
PubMed1990

Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro.

Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.

Adenine↗
PubMed1979

Left-sided colonoscopy in the office: a practical procedure.

Routine left-sided colonoscopy, instead of sigmoidoscopy, is a practical office measure. However, details of preparation and positioning of the patient are critical. The procedure has high productivity worth the added cost and effort. Cancer prevention is enhanced. Barium-enema examinations were found to have limited accuracy in polyp discovery, to a degree not previously appreciated.

Adult↗