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Biomedical subjects

George Thomas

Publications and source records attributed to George Thomas.

At least 19 recordsLinked to original sources
PubMed2006

Genetic background controls tumor development in PTEN-deficient mice.

PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Germ line mutations of PTEN have been detected in three rare autosomal-dominant disorders. However, identical mutations in the PTEN gene may lead to different symptoms that have traditionally been described as different disorders, such as Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndromes. This lack of genotype-phenotype correlation prompted us to directly test the possible effects of genetic background or modifier genes on PTEN-controlled tumorigenesis using genetically engineered mouse models. In this study, we generated two animal models in which either exon 5 (Pten(Delta5)) or promoter to exon 3 (Pten(-)) of the murine Pten gene were deleted and compared phenotypes associated with individual mutations on two genetic backgrounds. We found that the onset and spectrum of tumor formation depend significantly on the genetic background but less on the type of mutation generated. Our results suggest that PTEN plays a critical role in cancer development, and genetic background may influence the onset, the spectrum, and the progression of tumorigenesis caused by Pten mutation.

Alleles↗
PubMed2006

Hypothalamic mTOR signaling regulates food intake.

The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.

Animals↗
PubMed2006

The amino acid sensitive TOR pathway from yeast to mammals.

The target of rapamycin (TOR) is an ancient effector of cell growth that integrates signals from growth factors and nutrients. Two downstream effectors of mammalian TOR, the translational components S6K1 and 4EBP1, are commonly used as reporters of mTOR activity. The conical signaling cascade initiated by growth factors is mediated by PI3K, PKB, TSC1/2 and Rheb. However, the process through which nutrients, i.e., amino acids, activate mTOR remains largely unknown. Evidence exists for both an intracellular and/or a membrane bound sensor for amino acid mediated mTOR activation. Research in eukaryotic models, has implicated amino acid transporters as nutrient sensors. This review describes recent advances in nutrient signaling that impinge on mTOR and its targets including hVps34, class III PI3K, a transducer of nutrient availability to mTOR.

Amino Acids↗
PubMed2006

The voice handicap of student-teachers and risk factors perceived to have a negative influence on the voice.

A cross-sectional questionnaire survey was performed. The objectives of the study were to assess the psychosocial impact of current voice complaints as perceived by student-teachers with voice complaints in comparison with student-teachers without voice complaints, and to observe the pattern of risk factors in relation to their voice handicap. Subjects in the general population without a voice-demanding profession were selected as a reference group for limited comparison with the total group of student-teachers (future professional voice users). The respondents to the questionnaires were anonymous. Among the student-teachers, 17.2% reported current voice complaints in comparison with 9.7% of the reference group, and the odds ratio was 1.94, which showed the relative risk. Student-teachers had significantly greater total Voice Handicap Index (VHI) scores than the reference group (P = 0.034). The VHI subscale scores were not significantly different (P > 0.05). Student-teachers who reported current voice complaints had a significantly higher total VHI and subscale scores than student teachers without voice complaints (P < 0.001). Of the student-teachers without voice complaints, 17.0% had VHI scores greater than the 75th percentile. These persons may be neglecting their voice handicap and probably represent the false-negative cases in the estimation of voice complaints. Logistic regression analysis of each of the given risk factors with the VHI as the independent variable showed that the perceived negative influence of the given risk factors on their voices was significantly greater with increasing VHI scores across the VHI range. A significant correlation was observed between the number of perceived risk factors and increasing VHI scores across the VHI range. An increased awareness of risk factors in relation to their voice handicap would serve to motivate student-teachers to change factors that contributed to their voice problem. Attention to all risk factors, which the subjects perceive to be a risk, would aid in effective management of their voice handicap.

Adult↗
PubMed2006

Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. METHODS: Five subjects with clinically definite TSC and either subependymal giant cell astrocytomas (n = 4) or a pilocytic astrocytoma (n = 1) were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5-15 ng/ml) from 2.5 to 20 months. All lesions demonstrated growth on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. RESULTS: All lesions exhibited regression and, in one case, necrosis. Interruption of therapy resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further regression. Treatment was well tolerated. INTERPRETATION: Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions.

Adolescent↗
PubMed2006

Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1.

Nutrient overload leads to obesity, insulin resistance, and often type 2 diabetes. Whereas increased fat intake is commonly cited as the major factor in diet-induced dysmetabolic states, increased protein consumption also contributes, through elevated circulating amino acids. Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess.

Adipose Tissue↗
PubMed2006

Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications.

Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.

Carcinoma, Renal Cell↗
PubMed2006

Skin entrance radiation dose in an interventional radiology procedure.

Monitoring of skin entrance radiation exposure in lengthy interventional procedures has been recommended because of the potential for skin injury. Fluoroscopy duration and dose-area product (DAP) are readily available real-time measurements. It would be of interest to study the correlation of these parameters and skin entrance radiation. Twenty neurological interventional procedures performed through the aortic arch were monitored. Two pieces of GafChromic XR Type R film were placed between the patient and the examination table. An observer recorded the fluoroscopy duration and DAP for each phase of the procedure. Each film was scanned post-procedure in RBG mode, and then the image was analyzed for peak skin entrance radiation dose (in air kerma). All DAP values were corrected according to a calibration with an ion chamber. With the DAP values for the respective phases of a procedure, the effective dose in a Reference Man was calculated. For these twenty cases, the means and standard deviations were 17.2+/-6.4 min for x ray on-time, 256+/-65 Gy cm (-2) for DAP, 94+/-34 cGy for peak skin entrance dose in air kerma, and 19.2+/-5.0 mSv for effective dose, respectively. The peak skin entrance dose was correlated to fluoroscopy duration, DAP, and effective dose with the r(2)-values of 0.48, 0.46, and 0.09, respectively. The correlation with DAP or fluoroscopy duration was not sufficiently strong to infer skin entrance dose from either of these parameters. Therefore, skin entrance dose should be determined directly.

Film Dosimetry↗
PubMed2006

A working group classification of focal prostate atrophy lesions.

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.

Atrophy↗
PubMed2006

Prevalence of voice complaints, risk factors and impact of voice problems in female student teachers.

A cross-sectional questionnaire survey was done among 457 female student teachers and 144 females in the general population. The conclusions are based on the opinions of student teachers and the general population. The results of this study show that 39.6% of the student teachers and 32.6% of the general population reported voice complaints at the moment and/or over the past year (p=0.198). The association between various risk factors (vocal loading factors, physical factors, environmental factors and psycho-emotional factors) and voice complaints were examined. Vocal load was reported in both the student teachers and the general population (p=0.322). Among the subjects with voice complaints, the student teachers were significantly more of the opinion than the general population that environmental irritants in the classroom (p=0.001) and the composition of the group they communicate with (p=0.033) have a negative influence on their voice. In the groups with voice complaints, the student teachers reported significantly less than the general population that stress (p=0.004) and the deterioration of their general physical condition (p=0.003) have a negative influence on their voice. Remarkably, over a third of the student teachers and one fifth of the general population with voice complaints were of the opinion that decrease of hearing has a negative influence on their voices (p=0.113). There was no significant difference in Voice Handicap Index (VHI) scores (p=0.284) and impact of voice complaints among student teachers and the general population. Over 15% of the student teachers and the general population with voice complaints reported being or having been disabled due to the voice problem, probably reflecting the severity of the voice problem (p=0.838). The groups reporting voice complaints and disability in relation to their voice complaints have significantly higher VHI scores than those without voice complaints and disability, which indicates a higher psychosocial impact of voice complaints. Only around a third of the student teachers and the general population with voice complaints sought paramedical care (p=0.656)/treatment (p=0.361) for their voice complaint. Only a minority of student teachers (18.6%) and the general population (29.5%) with voice complaints were of the opinion that the number of people they communicate with has a negative influence on their voice (p=0.120). Only around a third of the student teachers and less than a tenth of the general population with voice complaints were of the view that they would develop a voice complaint due to their profession (p=0.003). Less than half of the student teachers and less than one fifth of the general population with voice complaints were aware of the potential risks of their profession on their voice (p=0.002). Voice complaints appear to have a multifactorial genesis. The student teachers are not sufficiently aware of the impact of the various risk factors on their voice. Furthermore, they are not aware of the potential risk that future teaching may have on their voice. This apparent lack of awareness in student teachers may be considered a risk factor for voice complaints.

Adolescent↗
PubMed2005

Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase.

During the evolution of metazoans and the rise of systemic hormonal regulation, the insulin-controlled class 1 phosphatidylinositol 3OH-kinase (PI3K) pathway was merged with the primordial amino acid-driven mammalian target of rapamycin (mTOR) pathway to control the growth and development of the organism. Insulin regulates mTOR function through a recently described canonical signaling pathway, which is initiated by the activation of class 1 PI3K. However, how the amino acid input is integrated with that of the insulin signaling pathway is unclear. Here we used a number of molecular, biochemical, and pharmacological approaches to address this issue. Unexpectedly, we found that a major pathway by which amino acids control mTOR signaling is distinct from that of insulin and that, instead of signaling through components of the insulin/class 1 PI3K pathway, amino acids mediate mTOR activation by signaling through class 3 PI3K, hVps34.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Measurement of dose-area product with GafChromic XR Type R film.

Many of the newer X-ray machines are equipped with electronic means to provide dose-area product (DAP) information. For machines without that ability, an alternative method is to record radiation on a film that can handle a large amount of cumulative exposure. The use of GafChromic XR Type R film was investigated for this purpose by placing it at the X-ray tube assembly to record the radiation in interventional radiological procedures. Dose-area product was determined with a reflective densitometer and then with a flatbed scanner. Precisions were demonstrated to be 5% and 2%, respectively. In a comparison with the machine-recorded DAP, a regression analysis showed the validity of both techniques for values less than 1200 Gy-cm2.

Algorithms↗
PubMed2005

Baseline neuropsychological profile and cognitive response to cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus.

OBJECTIVE: To evaluate neurocognitive changes and predict neurocognitive outcome after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus (INPH). BACKGROUND: Reports of neurocognitive response to shunting have been variable and studies that predict cognitive outcomes after shunting are limited. We reviewed our experience with cognitive outcomes for INPH patients who were selected for shunting based on abnormal cerebrospinal fluid (CSF) pressure monitoring and positive response in any of the NPH symptoms following large volume CSF drainage. METHODS: Forty-two INPH patients underwent neurocognitive testing and Folstein Mini-Mental State Examination (MMSE) prior to shunting. Neurocognitive testing or MMSEwere performed at least 3 months after shunt insertion. Significant improvement in a neurocognitive subtest was defined as improvement by one standard deviation (1 SD) for the patient's age, sex and education level. Significant improvement in overall neurocognitive outcome was defined as a 4-point improvement in MMSE or improvement by 1 SD in 50% of the administered neurocognitive subtests. Nonparametric tests were used to assess changes. Predictors of outcome were assessed via logistic regression analysis. RESULTS: Twenty-two patients (52.3%) showed overall neurocognitive improvement, and significant improvement was seen in tests of verbal memory and psychomotor speed. Predictive analysis showed that patients scoring more than 1 SD below mean at baseline on verbal memory immediate recall were fourfold less likely to show overall cognitive improvement, and sixfold less likely if also associated with visuoconstructional deficit or executive dysfunction. Verbal memory scores at baseline were higher in patients who showed overall cognitive improvement. CONCLUSIONS: Shunting INPH patients on the basis of CSF pressure monitoring and drainage response shows a significant rate of cognitive improvement, and baseline neurocognitive test scores may distinguish patients likely to respond to shunt surgery from those who will not.

Aged↗
PubMed2005

The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation.

Although DNA damaging agents have revolutionized chemotherapy against solid tumors, a narrow therapeutic window combined with severe side effects has limited their broader use. Here we show that RAD001 (everolimus), a rapamycin derivative, dramatically enhances cisplatin-induced apoptosis in wild-type p53, but not mutant p53 tumor cells. The use of isogenic tumor cell lines expressing either wild-type mTOR cDNA or a mutant that does not bind RAD001 demonstrates that the effects of RAD001 are through inhibition of mTOR function. We further show that RAD001 sensitizes cells to cisplatin by inhibiting p53-induced p21 expression. Unexpectedly, this effect is attributed to a small but significant inhibition of p21 translation combined with its short half-life. These findings provide the molecular rationale for combining DNA damaging agents with RAD001, showing that a general effect on a major anabolic process may dramatically enhance the efficacy of an established drug protocol in the treatment of cancer patients with solid tumors.

Antineoplastic Agents↗
PubMed2005

Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus.

OBJECTIVE: The response to shunt surgery for idiopathic normal-pressure hydrocephalus (INPH) is variable because INPH is difficult to distinguish from other conditions causing the same symptoms. To date, no clinical picture or diagnostic test can distinguish INPH or predict response to cerebrospinal fluid (CSF) shunt surgery. We reviewed our 10-year experience with INPH to characterize long-term outcome and to identify independent predictors of outcome after shunt surgery. METHODS: Patients were classified as having INPH only if they had: 1) ventriculomegaly, 2) two or more INPH clinical features, 3) no risk factor for secondary normal-pressure hydrocephalus, 4) A- or B-waves on CSF pressure monitoring, and 5) clinical improvement during a 3-day CSF drainage trial via a spinal catheter. Independent predictors of outcome were assessed via a multivariate proportional hazards regression analysis. RESULTS: One hundred thirty-two patients underwent 179 shunt surgeries. Forty-four (33%), 79 (60%), and 99 (75%) patients demonstrated objective improvement 3, 6, and 24 months after shunt surgery, respectively. Gait improved first in 88 (93%) patients. Dementia and urinary incontinence were twofold less likely to improve. Radiological evidence of corpus callosum distension, gait impairment as the primary symptom, and shorter duration of INPH symptoms predicted improvement. Duration of symptoms and gait as the primary symptom were independent predictors by multivariate analysis. CONCLUSION: INPH can be diagnosed accurately with CSF pressure monitoring and CSF drainage via a spinal catheter. CSF shunting is safe and effective for INPH with a long-term shunt response rate of 75%. Independent predictors of improvement are the presence of gait impairment as the dominant symptom and shorter duration of symptoms.

Aged↗