Role of germ line p53 mutations in aneuploidy and immortalization of dermal fibroblasts from Li-Fraumeni cancer patients

Pedigree analysis of certain families with a high incidence of tumors suggests a genetic predisposition to cancer. Li and Fraumeni described a familial cancer syndrome that is characterized by multiple primary tumors, early age of onset, and marked variation in tumor type. Williams and Strong (1) demonstrated that at least 7% of childhood soft tissue sarcoma patients had family histories that is readily explained by a highly penetrant autosomal dominant gene. To characterize the mechanism for genetic predisposition to many tumor types in these families, we have studied genetic alterations in fibroblasts, a target tissue from patients with the Li-Fraumeni Syndrome (LFS).^ We have observed spontaneous changes in initially normal dermal fibroblasts from LFS patients as they are cultured in vitro. The cells acquire an altered morphology, chromosomal anomalies, and anchorage-independent growth. This aberrant behavior of fibroblasts from LFS patients had never been observed in fibroblasts from normal donors. In addition to these phenotypic alterations, patient fibroblasts spontaneously immortalize by 50 population doublings (pd) in culture; unlike controls that remain normal and senesce by 30-35 (2). At 50 pd, immortal fibroblasts from two patients were found to be susceptible to tumorigenic transformation by an activated T24 H-ras oncogene (3). Approximately 80% of the oncogene expressing transfectants were capable of forming tumors in nude mice within 2-3 weeks. p53 has been previously associated with immortalization of cells in culture and cooperation with ras in transfection assays. Therefore, patients' fibroblast and lymphocyte derived DNA was tested for point mutations in p53. It was shown that LFS patients inherited certain point mutations in one of the two p53 alleles (4). Further studies on the above LFS immortal fibroblasts have demonstrated loss of the remaining p53 allele concomitant with escape from senescence. While the loss of the second allele correlates with immortalization it is not sufficient to transformation by an activated H-ras or N-ras oncogene. These immortal fibroblasts are resistant to tumorigenic transformation by v-abl, v-src, c-neu or v-mos oncogene; implying that additional steps are required in the tumorigenic progression of LFS patients' fibroblasts.^ References. (1) Williams et al., J. Natl. Cancer Inst. 79:1213, 1987. (2) Bischoff et al., Cancer Res. 50:7979, 1990. (3) Bischoff et al., Oncogene 6:183, 1991. (4) Malkin et al., Science 250:1233, 1990. ^

Eye movements discriminate fatigue due to chronotypical factors and time spent on task--a double dissociation

Systematic differences in circadian rhythmicity are thought to be a substantial factor determining inter-individual differences in fatigue and cognitive performance. The synchronicity effect (when time of testing coincides with the respective circadian peak period) seems to play an important role. Eye movements have been shown to be a reliable indicator of fatigue due to sleep deprivation or time spent on cognitive tasks. However, eye movements have not been used so far to investigate the circadian synchronicity effect and the resulting differences in fatigue. The aim of the present study was to assess how different oculomotor parameters in a free visual exploration task are influenced by: a) fatigue due to chronotypical factors (being a 'morning type' or an 'evening type'); b) fatigue due to the time spent on task. Eighteen healthy participants performed a free visual exploration task of naturalistic pictures while their eye movements were recorded. The task was performed twice, once at their optimal and once at their non-optimal time of the day. Moreover, participants rated their subjective fatigue. The non-optimal time of the day triggered a significant and stable increase in the mean visual fixation duration during the free visual exploration task for both chronotypes. The increase in the mean visual fixation duration correlated with the difference in subjectively perceived fatigue at optimal and non-optimal times of the day. Conversely, the mean saccadic speed significantly and progressively decreased throughout the duration of the task, but was not influenced by the optimal or non-optimal time of the day for both chronotypes. The results suggest that different oculomotor parameters are discriminative for fatigue due to different sources. A decrease in saccadic speed seems to reflect fatigue due to time spent on task, whereas an increase in mean fixation duration a lack of synchronicity between chronotype and time of the day.

Mafteaḥ li-melekhet shire ha-ḳodesh : ...

In publicum emissa Per M. Hieronymum Avianum

Ketavim li-bene ha-neʿurim

Sh. Ben-Tsiyon. Metsuyarim ʿal yede N. Guṭman

Król "Gebalim" w liście Chasdaja : studyum historyczne z.x.w.

napisał Teofil Emiol Modelski

Modaʻ li-vene binah oder Kinderfreund und Lehrer : ein Lehr- und Lesebuch für die Jugend jüdischer Nation und für jeden Liebhaber der hebräischen Sprache

von Moses Philippssohn

Characterisation of a Natural Quartz Crystal as a Reference Material for Microanalytical Determination of Ti, Al, Li, Fe, Mn, Ga and Ge

A natural smoky quartz crystal from Shandong province, China, was characterised by laser ablation ICP-MS, electron probe microanalysis (EPMA) and solution ICP-MS to determine the concentration of twenty-four trace and ultra trace elements. Our main focus was on Ti quantification because of the increased use of this element for titanium in- quartz (TitaniQ) thermobarometry. Pieces of a uniform growth zone of 9 mm thickness within the quartz crystal were analysed in four different LA-ICP-MS laboratories, three EPMA laboratories and one solution-ICP-MS laboratory. The results reveal reproducible concentrations of Ti (57 ± 4 lg g-1),Al (154 ± 15 lg g-1), Li (30 ± 2 lg g-1), Fe (2.2 ± 0.3 lg g-1), Mn (0.34 ± 0.04 lg g-1), Ge (1.7 ± 0.2 lg g-1) and Ga (0.020 ± 0.002 lg g-1) and detectable, but less reproducible, concentrations of Be, B, Na, Cu, Zr, Sn and Pb. oncentrations of K, Ca, Sr, Mo, Ag, Sb, Ba and Au were below the limits of detection of all three techniques. The uncertainties on the average concentration determinations by multiple techniques and laboratories for Ti, Al, Li, Fe, Mn, Ga and Ge are low; hence, this quartz can serve as a reference material or a secondary reference material for microanalytical applications involving the quantification of trace elements in quartz.

Liḳute shoshanim : ṿe-hu reshimat ha-sefarim

asher asaf ṿe-ḳavats ... Matatyahu Shtrashun ...

Le-Shabat ṿe-li-yeme ḥol

Für Kantor und Chor a cappella

Sēfer Menôrat ham-mā'ôr : we-ze maʿaśē ham-menôrā ʿim 7 nērôt ... ʿim haʿtāqā li-lšôn aškenaz

ḥibberô ... Yiṣḥāq Abôhab

Sēfer Menôrat ham-mā'ôr : we-ze maʿaśe ham-menôrā ʿim 7 nērôt ... ʿim haʿtāqā li-lšôn aškenaz ...

ḥibberô ... Yiṣḥāq Abôhab

Sēfer Menôrat ham-mā'ôr : we-ze maʿaśe ham-menôrā ʿim 7 nērôt ... li-lšôn aškenaz

Yiṣḥāq Abôhab

Sēfer Menôrat ham-mā'ôr : ... û-le-maʿan gam nāšîm we-yelādîm yiʿidû li-šmôaʿ be-limmûdîm ...

Yiṣḥāq Abôhab

Sēfer Menôrat ham-mā'ôr : we-ze maʿaśe ham-menôrā ... ʿim haʿtāqā li-lšôn aškenaz

ḥibbērô ... Yiṣḥāq Abôhab