The Effect of Gefitinib on B-RAF Mutant Non-small Cell Lung Cancer and Transfectants

Abstract:We previously reported one patient with squamous cell carcinoma of the lung that showed the long-term effect to gefitinib with complete response. In the present report, we examine the epidermal growth factor receptor (EGFR) and K-RAS, HER2, and B-RAF mutations in this patient to find a B-RAF exon11 mutation, resulting in a substitution of valine by phenylalanine at codon 470 (V470F) as a novel type of B-RAF mutation in human cancers. In addition, the fluorescence in situ hybridization analysis for EGFR showed the high polysomy status. B-RAF is a nonreceptor serine/threonine kinase whose kinase domain has a structure similar to other protein kinases, including EGFR members. Of interest, the B-RAF V470F mutation corresponds to a position similar to the EGFR G719X mutation located on the phosphate binding (P)-loop of EGFR that clamps ATP into the catalytic cleft. This observation suggests that gefitinib may have an anti-cancer effect on B-RAF mutant tumors. Indeed, previous reports demonstrated that H1666 cells harboring B-RAF G465V mutations showed sensitivity to gefitinib, inhibiting phosphorylation of ERK1/2. We examined the effect of gefitinib on transient transfectants of the B-RAF mutant, but no drastic inhibition of ERK1/2 phosphorylation that was one of the downstream molecules of B-RAF was induced by gefitinib.In summary, we found a novel B-RAF V470F mutation in lung squamous cell carcinoma that showed response to gefitinib. However, our in vitro investigation did not explain the response observed in this particular patient. Further investigation is necessary to elucidate the mechanism of tumor sensitivity to EGFR tyrosine kinase inhibitors

低酸素下の最大運動において、運動前の低酸素暴露時間の違いが血漿アンモニア濃度に及ぼす影響

The purpose of this study was to investigate the effect of a difference in hypoxic exposure duration before exercise on maximum plasma ammonia concentrations at maximal exercise in hypoxia. On three occasions, seven healthy male subjects performed an incremental exhaustive exercise on a cycle ergometer ; 1) Inhaling 12% O_2 from 60min before exercise to 10 min after exercise (HP60) ; 2) inspiring 12% O_2 from 10 min before exercise to 10 min after exercise (HP10) ; and 3) Inhaling air (MAX). Arterialized blood was drawn from a superficial arm vein. Arterial O_2 saturation (SaO_2), blood gas, plasma lactate, and plasma ammonia were determined. SaO_2 before exercise was lower in HP60 than that in HP10 (P<0.001). Blood Ph before exercise was lower in HP60 than that in MAX (P<0.05). Maximum plasma lactate concentrations were the same levels in all three tests. Maximum plasma ammonia concentration in HP60 was lower than that in MAX (P<0.01), while that in HP10 did not differ from that in MAX. From these results we suggest that a longer duration of hypoxic exposure before exercise may have resulted in a lower SaO_2 and a stronger respiratory alkalosis, maximum ammonia concentration which has lead a lower at maximal exercise in hypoxia

ストレス蛋白 (HSP 70) が運動による筋損傷・筋疲労の修復に及ぼす影響

Current interest is attracted to the problem on the correlation between physical exercise and heat shock induced protein (HSP 70), especially on the enhanced postischemic myocardial recovery following exercise induction of HSP 70. From the recent papers, the inducible isoform of the 70kDa heat shock protein (HSP) family, HSP 70kDa has been confirmed to protect cells from protein-damaging stressors and has been associated with not only myocardial protection but also recovery of several tissue damages. In the present review article, therefore, the related papers to exercise induced body hyperthermia, muscular damage and HSP 70 family, and their protection and/or recovery mechanism were collected and analyzed from the view-points of biological functions of stress protein HSP 70 family as well as of Granyl-Granyl Acetone (GGA) the HSP inducer

水分補給による持久性運動パフォーマンスの修飾 : 特に水分量・グルコース・電解質の相互関係

Considerable interest is attracted to the problems on water ingestion during exercise, however, it is still hypothesis that water ingestion would attenuate the exercise-induced increase in thermoregulatory mechanism such as rectal and muscle temperatures and plasma epinephrine, thereby resulting in less net muscle glycogen utilization. In the present review article, therefore, the hypothesis was discussed and confirmed by the results of 25 important papers related to the problems of improvement of physical performance based on the following three papers : (1) Effects of fluid ingestion during intermittent high intensity swimming exercise on thermoregulatory response and performance. (2) Effect of fluid ingestion on muscle metabolism during prolonged exercise. (3) Heat stress increases muscle glycogen use but reduces the oxidation of ingested carbohydrates during exercise. These review articles indicate that fluid ingestions reduces muscle glycogen use during prolonged exercise, which may account in part, for the improved performance in the hypothesis mentioned above

種々の極限環境条件下における生体反応の適応耐性

On the occasion of the International Thermal Physiology Symposium in Rhodes (2004), Extremes of human thermo-tolerance and adaptation to high altitudes were reviewed for sports scientists and thermal physiologists as follows ; Human life is sustainable only below an internal temperature of roughly 42-44℃. Yet our ability to survive at severe environmental extremes is testimony to the marvels of integrative human physiology. One approach to understanding human thermoregulatory capacity is to examine the upper limits of thermal balance between man and an air-water environment, i.e. the maximal environmental conditions under which humans can maintain a steady-state core temperature. Heat and cold acclimations expands the zone of thermal balance. Human beings can and do, often willingly, tolerate extreme heat and cold (incl. Low atmospheric pressure) stresses well above these thermal balance limits. Survival in all such cases is limited to abbreviated exposure times, which in turn are limited by the robustness of the thermoregulatory response. High altitudes are associated with low temperature as well as low pressure. Chronic exposure to high altitudes is known to cause physiological and morphological changes, especially in the pulmonary circulation system, such as right ventricular hypertrophy, pulmonary hypertension, increased, pulmonary vascular resistance, thickening of the pulmonary artery and increased pulmonary blood flow. The principal factors in these change are hypoxic pulmonary vasoconstriction (HPVC) and an elevation of hematocrit (Ht) accompanying the increase in red blood cell (RBC). Figures in this review article are provided that relate tolerance time and the rate of change in core temperature to environmental characteristics based on data compiled from the literature of scientific journals and records published in the Guinness Book

頭寒足熱の温熱生理学的検証

Biological responses due to thermal stimuli were categorized based on the areas of the human body as well as on the modalities of thermal stresses such as icing, cooling and heating applications. These biological responses reported in previous papers were analyzed based on the concepts of Selective Brain Cooling (SBC) and long-term fever range (FR)-mild hyperthermia. Although no thermophysiological problems occurred in the case reports of biological responses induced by SBC, the effects of those induced by cooling of the body trunk and extremities were not so thoroughly evaluated. On the other hand, the idea of long-term fever range (FR)-mild hyperthermia (39.5-41.0℃) proved to be helpful in therapies enhancing the immune defenses against virulent bacterial diseases through the proliferation of Langerhans cells (LCs) and, under these conditions, it might even be beneficially combined with Selective Brain Cooling (SBC) and body heating to enhance human health and physical performance

ストレス環境下におけるヒト高体温の誘発と抑制機序 : ヒト最高体温の再検索

Biological functions are basically dependent on the thermosensitive characteristics of the proteins and fatty substances composing the body structure. In a stressful environment, the extremely high human body temperatures detected by computer system in our laboratory of Exercise Physiology are in the range of 41℃-46.5℃, of which the highest temperature was identical with the highest value described in the latest Guinness Book of Records. The highest body temperature value of 46.5℃ reported in Ann Emerg Med (1982) is thought to be extremely high compared to those of the other vertebrates. The concept of critical thermal maximum (CTM) has been defined in the present literature as the minimal high deep-body temperature that is lethal to an animal. In man the CTM has been estimated at 41.6-42.0℃. Therefore, in the present review article, physiological, pathological and clinical cases of hyperthermia beyond 42℃ detected in 49 papers, and the biological inhibitory mechanisms preventing hyperthermia and the immunological protection mechanisms associated with strong heat stresses were discussed from the viewpoint of the negative feed back system that controls body temperature