Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors.

The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.

Mental health in older adult recipients of primary care services: is depression the key issue? Identification, treatment and the general practitioner.

OBJECTIVES: Mental health services for older people in primary care are relatively underdeveloped. This study has sought to determine the nature and extent of mental health problems in older people presenting to primary care and to compare this with the detection and management of mental health problems by the primary health care team (PHCT). METHOD: Participants were patients aged 65 years and above attending a representative inner city general practice. Screening tools included the General Health Questionnaire (GHQ-28), Hospital Anxiety and Depression Scale (HADS), Mini Mental State Examination (MMSE). The PHCT used a brief checklist to rate participants for the presence of mental health problems. Follow-up interviews using the Geriatric Mental State (GMSA), Cambridge Examination for Mental Disorders in the Elderly (CAMDEX)-cognitive subscale (CAMCOG), National Adult Reading Test (NART), were carried out. RESULTS: A high level of psychological morbidity was identified at screening (48.1%). There was a considerable degree of agreement between the HADS and GMSA, and the MMSE and GMSA at follow-up. Agreement rates between the PHCT and initial screening tools were low suggesting under-recognition of mental health problems at primary care level by the PHCT. Contributory factors included: short consultation times with a concentration on physical symptoms; few patients presenting explicitly with mental health problems; few decisions to treat or refer patients; and the general practitioners tended to monitor, or defer decisions. CONCLUSIONS: This study found lower levels of severe mental health problems, especially depression, than reported elsewhere, but higher prevalence of psychological distress. High levels of physical and mental health co-morbidity were found. These findings suggest that planning for primary care services needs to adopt a flexible assessment model. The development of effective, time-limited protocols and screening tools to assist the PHCT in improving their identification rates is recommended. This needs to be supported by the availability of appropriate treatments for the psychological distress.

Haptic discrimination of size and texture in squirrel monkeys (Saimiri sciureus).

The present study analyzed haptic abilities of four squirrel monkeys. Using a two-alternative forced-choice procedure, stimuli were presented in a visually opaque box, allowing unrestrained test subjects to grab through a small opening and touch the discriminanda. Difference thresholds were determined by a modified method of limits. In the first experiment we determined size difference thresholds for the discrimination of circular cylinders using standard stimuli differing in diameter from 10 mm to 35 mm. In the second experiment a texture difference threshold was obtained for the discrimination of grooved surfaces (groove width 2-7 mm). The squirrel monkeys achieved a mean size difference threshold of 8% stimulus difference. The linear increase of absolute thresholds as a function of the starting stimulus size showed that haptic size discriminations in squirrel monkeys correspond to Weber's law. Three of the animals achieved a texture difference of 10% stimulus difference, while one monkey showed a distinctively lower haptic acuity. An analysis of the exploratory behavior points to a subject-related difference in the significance of cutaneous and kinesthetic information during size discriminations. Whereas differences in the animals' exploratory behavior did not correlate with the size difference threshold a subject achieved, different thresholds for texture discrimination can be explained by the different exploratory procedures the monkeys used to touch grooved surfaces. The low difference thresholds determined for the squirrel monkeys in the present study point to the significance of unrestrained test conditions for the assessment of the haptic capacity of a species.

Dissociation of spatial reference memory, spatial working memory, and hippocampal mossy fiber distribution in two rat strains differing in emotionality.

Rats of the inbred strains DA/Han and BDE/Han were compared on two complex spatial learning tasks, a spatial reference memory task in a 16-unit multiple T-maze and a spatial working memory task in an eight-arm radial-maze. In addition, sizes of hippocampal mossy fiber terminal fields were measured. BDE rats showed marked superiority in multiple T-maze learning whereas DA rats outperformed BDE rats on the radial-maze task. DA rats had significantly larger intra- and infrapyramidal mossy fiber terminal fields (IIP-MF). This is consistent with findings from other studies suggesting that large IIP-MF are related to excellent spatial radial-maze learning, but it also indicates that size of IIP-MF is correlated with processing of a specific type of spatial information rather than with overall spatial abilities. BDE rats had more extended suprapyramidal mossy fiber projections (SP-MF) and a larger hilus. Rats of both strains differed in exploratory behaviour and emotionality: DA rats revealed little freezing and had a high rearing activity, whereas BDE rats showed frequent freezing and reared rarely. Results suggest that IIP-MF are involved with flexible expression of memory, updating environmental information and parallel processing whereas SP-MF might be linked to processing of familiar information. Presumably, emotional factors contribute to performance differences.

[The effect of the distribution of practice on the learning and forgetting in Carassius auratus auratus Linné]. / Die Auswirkung der Ubungsverteilung auf das Lernen und Vergessen bei Carassius auratus auratus Linné.

The significance of massed and distributed practice in discrimination learning to criterion by goldfish was studied. All animals were trained to discriminate between 6 horizontal black and white stripes (positive stimulus) and 2 vertical black and white stripes (negative stimulus). 5 groups of animals, 12 Ss each, got different training programs. Groups varied in number of trials per day (30, 10, 5 successive trials) and in distribution of trials over the day (30 trials given in blocks of 5 with ITI of 1 h or 5 trials, each spaced by an ITI of 1 h). In general animals with a small number of massed trials/day were superior in early acquisition period. When trials/day were spaced the method proved to be more efficient. The training method showed no effect concerning retention.

[Classical conditioning of agonistic behavior in the Syrian golden hamster (Mesocricetus auratus Waterhouse)]. / Klassische Konditionierienz agonistischen Verhalten beim Syrischen Goldhamster (Mesocricetus auratus Waterhouse).

Nine different reactions of unconditioned agonistic behavior of golden hamsters (Mesocricetus auratus Waterhouse) which could be elicited by an air blow (UCS) were classically conditioned at a sound of a xylophone (tone g), a previously neutral stimulus. Tone g (CS) was paired with UCS for a different number of trials/day. In all animals exposed to over 20 pairings/day components of the agonistic behavior were brought under the control of CS, but it was not possible to predict which one of the agonistic reactions would appear. Most of the animals generalized and also showed conditioned reactions (CR) when presenting tone c' instead of tone g. When utilizing a differential conditioning procedure the animals learned to discriminate between the different tones. Extinction of CR at tone g was reached after an individually different number of trials.

[Age-specific learning ability in Japanese quails (Coturnix coturnix japonica)]. / Altersabhängiges Lernen bei der Japanischen Wachtel (Coturnix coturnix japonica)

The main question of our investigation is: Do there exist age-specific learning abilities in animals? 120 QUAILS (Coturnix coturnix japonica) of 12 different age groups (between one day and 20 weeks) were tested in a combination apparatus 0y using two training methods. 60 quails were trained with decreasing (1), 60 other quails with increasing learning assistance (2). In each case the learning period lasted 5 days after which the animals were tested in a two-way choice apparatus and in a simple maze. Retention was tested 3 weeks later. - The 2 methods led to different results. In general the younger animals learnt better than the other ones when trained by method 1. No differences in learning performance between the 12 age groups were obtained by method 2.