Gloria C. Li

Induced thermal tolerance and heat shock protein synthesis in Chinese hamster ovary cells.

Abstract We have performed experiments to determine the kinetics of induction of thermal tolerance in Chinese hamster HA-1 cells, and the effects of heat treatments on the recovery of protein synthesis, with particular attention to whether heat induces specific proteins, perhaps the heat shock proteins (HSP). The kinetics of the development of thermal tolerance were measured by increases in cellular survival. In parallel experiments, the effects of heat treatment on the recovery of protein synthesis in HA-1 cells were examined. After heating (45°, 20 minutes), some of these cells were immediately labeled with 35 S-methionine (10 μCi/ml) for 1 hour at 37°, while the others were incubated at 37° for 1–8 hours and then labeled. The cell samples were prepared for electrophoresis on a gradient SDS gel. The incorporation of label into HA-1 cell proteins was drastically inhibited by the 45° heat treatment, but recovered gradually during the 8-hour incubation period at 37°C. A comparison of the proteins synthesized following heat shock with those synthesized by non-heated cells showed that the levels of synthesis of certain proteins were greatly enhanced following the 45° treatment. By 8 hours, it was qualitatively apparent that three proteins, with molecular weights of 59K, 70K and 87K, were synthesized in greater amounts than in untreated cells. The kinetics of HSP synthesis were compared to the kinetics of thermal tolerance; these showed good correlation. Overall protein synthesis also increased during this time, although at a rate slower than the synthesis of the HSP. The question of whether the HSP play a causative role in the development of thermal tolerance and if so, what that role might be, has not been answered.

Temperature-induced homeoviscous adaptation of Chinese hamster ovary cells.

Exponential and plateau phase Chinese hamster ovary cells were maintained for 3 days at 32, 37, 39 or 41 degrees C. The effect of growth temperature on the fluidity and composition of the cellular membranes, and on the ability of the cells to resist a subsequent heat treatment at 43 degrees C, was measured. Cells grown at temperatures above 37 degrees C displayed increased resistance or tolerance to a 43 degree C heat treatment, whereas cells grown at 32 degrees C were sensitized to heat. Extensive cell division was not required for expression of heat tolerance. Membrane fluidity, as determined by the degree of rotational mobility of the fluorescent probe diphenylhexatriene, decreased with increasing growth temperatures, but the relationship did not hold in exponential phase cells grown at 32 degrees C. The cholesterol : phospholipid molar ratio correlated with the fluorescence polarization values, suggesting that the cells are able to adjust membrane fluidity by varying the concentration of cholesterol. The results are compatible with the concept of homeoviscous adaptation: that organisms strive to maintain an optimal level of membrane fluidity and when grown at a different temperature will alter the lipid composition in order to maintain this level. Up until now, cholesterol has not been implicated in this process.

Effect of Hyperthermia on the Radiation Response of two Mammalian Cell Lines

Abstract The interaction of 43° C hyperthermia and X-irradiation was compared in vitro in two cell lines: Chinese hamster ovary (HA- 1 ) and mouse mammary sarcoma (EMT- 6 ). In HA- 1 cells the sequence of heating followed by X-irradiation resulted in appreciably more sensitization than the opposite sequence; in EMT- 6 cells the opposite occurred. When time at 37° C was introduced between the two treatments, the degree of interaction was reduced, depending upon sequence and the duration of the 37° C time interval. In both cell lines, maximum toxicity was seen if the two treatments followed each other immediately.

High energy elastic electron scattering from 24Mg, 28Si and S☆

Abstract High momentum transfer elastic electron scattering data (q = 0.8 – 3.7 fm−1) from 24Mg, 28Si and S are presented and analysed with phenomenological charge distributions ϱ(r); and oscillation in ϱ(r) due to shell-model structure is obtained. An analysis in terms of a Woods-Saxon potential is described and the 2s-1d occupation numbers are deduced.

Introduction to the use of negative pi-mesons in radiation therapy: Rutherford 1964, revisited☆

Abstract The existence of negative pi-mesons was predicted from considerations of infra-nuclear binding forces by Yukawa in 1935. Direct evidence for these unique particles was discovered during cosmic ray research by Lattes, Occhialini and Powell in 1947. I understand that the possibility that pions might be useful in radiation therapy was discussed by Drs. Chaim Richman and Cornelius Tobias here in Berkeley in about 1952. The fist detailed easy on this possibility, by P. H. Fowler and D. H. Perkins, appeared is Nature in 1961 and predicted many of the pertinent characteristics of the potential therapeutic usefulness of negative pi-mesons. Fowler described these in further detail in the 1964 Rutherford Memorial Lecture, entitled “Pi Mesons Versus Cancer.” These articles stimulated a search for appropriate methods for production of pi-mesons in sufficient quantity for consideration of human therapy. Unfortunately, as the requirements for such a device are severe, it was not until recently that particle accelerators with sufficiently high beam currents became available. Thus, clinically useful pion channels have been added to proton accelerators at Los Alamos and Vancouver. In addition, a high-yield pion concentrator has been constructed at Stanford for use with a high-intensity electron beam, and this is being adapted in Zurich for use with a proton beam. Preliminary treatment planning, using the known characteristics of pion beams, has yielded interesting and apparently unique treatment plans which promise higher biological dose to the target volume and greater protection to normal tissues. This combination may offer greater opportunity for control of neoplasms at the primary site and also control of such neoplasms as carcinoma of the pancreas and osteosarcoma, known poor responders to conventional high-energy X-irradiation.

Clinical dosimetry for negative pi mesons.

The authors describe a multichannel negative pi meson source for radiation therapy. A series of treatment plans was developed, using only parameters within the design capabilities of this device. The pion-equivalent isodose contours demonstrate a remarkable ability to limit the high-dose region to the tumor target volume, with a rapid fall-off in dose to the normal surrounding tissues.

Treatment planning for negative pi-meson radiation therapy: Simultaneous multi-port irradiation with the Stanford Medical Pion Generator (SMPG)

Abstract The cylindrical geometry of the Stanford Medical Pion Generator (SMPG) offers promise in achieving pion star fractions from 0.57 to 0.67 within the tumor volume and tumor to entrance region dose ratios of greater than 25:1 for tumor volumes up to 10 cm dia. The star fractions and tumor to entrance region dose ratios decrease slightly with increasing tumor diameters in the same water phantom but do not change for the same tumor diameter in water phantoms with radii from 10 to 20 cm. Although the radial pseudo-penumbrae (distance between the 90% and 20% isodose lines) for 60 beams with a ±2% momentum spread are 2.6 and 3.1 cm for 15 and 20 cm range (in water) pion beams, the dose distributions are superior to those achievable with X-rays and neutrons. In addition, the sparing of normal tissues can be further improved by selectively omitting some of the 60 pion beams, by using a smaller momentum spread or by using pious of lower mean momentum. The tailoring of the irradiation volume along the axis of symmetry of the SMPG is influenced primarily by the length of the pion production target and will require a compromise between the ideal tumor volume configuration and the inherent focal properties of the SMPG. Thus each treatment plan will require careful consideration of the numerous interrelationships between the physical characteristics of the patient and tumor volume and the treatment parameters of the SMPG.

A Phase I/II Trial of 5 Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma Multiforme.

The spine cases included a fifth lumbar spine (case 1), fifth thoracic spine (case 2), and 10th thoracic spine metastases (case 3). Targets and organs at risk (OAR) were contoured by one experienced radiation oncologist according to International Spine Radiosurgery Consortium Consensus Guidelines and a 2 mm planning target volume (PTV) applied. The DICOM files were sent to each institute for planning. The treatment planning guidelines in the previous study included, prescribed dose of 24 Gy in two fractions with more than 70% prescribed dose to encompass D95, D0.035 <140% of the prescribed dose, and a maximum dose to the spinal cord planning organ at risk volume (PRV) or thecal sac <17 Gy. New guidelines added (D95 should be as high as possible (AHAP), D50 should be between 110% and 115% of prescribed dose and AHAP and D0.035 should be between 125% and 135% of the prescribed dose). The dose volume histograms (DVHs) were centrally reviewed. Results: In our previous study the PTV D95 ranged from 70.0% to 99.6% in case 1 (mean SD; 21.21 2.43 Gy), 70.4% to 98.8% in case 2 (20.32 2.22 Gy), and 70.0% to 94.2% in case 3 (19.78 1.97 Gy), respectively, and D50 for PTV ranged from 99.2% to 116.3% in case 1 (25.62 1.34 Gy), 91.7% to 119.6% in case 2 (25.97 2.18 Gy) and 84.2% to 114.2% in case 3 (25.57 2.14 Gy), respectively. In this study PTV D95 ranged from 80.4% to 100.0% in case 1 (21.96 1.67 Gy), 76.3% to 95.8% in case 2 (20.91 1.67 Gy), and 70.4% to 94.2% in case 3 (20.3 1.86 Gy), respectively and D50 for PTV ranged from 109.6% to 115.4% in case 1 (27.02 0.53 Gy), 110.0% to 117.5% in case 2 (27.06 0.63 Gy) and 107.5% to 115.0% in case 3 (26.89 0.67 Gy), respectively. Conclusion: We succeeded to minimize the inter-institutional variations. This study highlights dose constraints of D95, D50, and D0.035 should be used to minimize the variations. Author Disclosure: H. Tanaka: None. T. Furuya: None. Y. Kumazaki: None. M. Nakayama: None. H. Nishimura: None. M.E. Ruschin: None. D. Pinnaduwage: None. J. Phua: None. I. Thibault: None. J. StHilaire: None. L. Ma: None. A. Sahgal: None. N. Shikama: None. K. Karasawa: None.

Basic considerations in simulated treatment planning for the Stanford Medical Pion Generator (SMPG).

Recent interest in charged heavy particle irradiation is based upon expected improved local tumor control rates because of the greater precision in dose localization and the increased biological effectiveness of the high linear energy transfer ionization of particle beams in their stopping regions (Bragg peaks). A novel 60 beam cylindrical geometry pion spectrometer designed for a hospital-based pion therapy facility has been constructed at Stanford. In conjunction with the development and testing of the SMPG a program of simulated treatment planning is being conducted. This paper presents basic considerations in treatment planning for pions and other charged heavy particles. It also presents the status of simulated treatment planning calculations for the SMPG including a discussion of the principle of irradiation of hypothetical tumor volumes illustrated by examples of simplified treatment plans incorporating tissue density inhomogeneity corrections. Also presented are considerations for realistic simulated treatment planning calculations using computerized tomographic scan cross sections of actual patients and a conceptual plan for an integrated treatment planning and patient treatment system for the SMPG.

The desirability of treatment with multiple fields in charged heavy particle therapy

The influence of the physical characteristics and biological effectiveness of pion and other charged heavy particle beams on treatment techniques is reviewed. Of major importance are the expected differences in the biological effects of variable star dose to total dose ratios (star fractions) with pion beams and with high LET to low LET dose ratios with other charged particles. Special consideration is given to the multiport irradiation configuration of the Stanford Medical Pion Generator.