tbuckley/cabot-search huggingface dataset:
The BRAFV600E Oncogene Induces Transforming Growth Factor β Secretion Leading to Sodium Iodide Symporter Repression and Increased Malignancy in Thyroid Cancer
Authors: Garcilaso Riesco-Eizaguirre, Irene Rodríguez, Antonio De la Vieja, Eugenia Costamagna, Nancy Carrasco, Manuel Nistal, Pilar Santisteban
Journal: Cancer Research (2009)

Abstract The activating mutation BRAFV600E is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)β loop. BRAF induces secretion of functional TGFβ and blocking TGFβ/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFβ cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFβ and other key components of TGFβ signaling, such as TβRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFβ. Moreover, this high TGFβ/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFβ is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFβ and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFβ may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression. [Cancer Res 2009;69(21):8317–25]
Acting in good taste: nutrient sensors in the gut
Authors: K. S Yan, P. J. Pasricha
Journal: Gut (2009)

Our senses help us perceive the external environment and respond appropriately to external cues. Many of our senses, including our sense of taste, use G-protein coupled receptors (GPCRs) for transduction of environmental signals. Taste sensation is mediated through two families of related, evolutionarily conserved GPCRs known as T1Rs and T2Rs, originally described within taste buds of the tongue.1 Through these basic elements, we are able to generate a diverse repertoire of taste sensations including sweet, bitter and savoury (umami) tastes. For example, sweet taste sensation is initiated by ligand binding to the extracellular domain of the heterodimeric receptor complex formed by the GPCRs T1R2 and T1R3, whereas savoury taste sensation is initiated through a heterodimer of T1R1 and T1R3.1 The activated intracellular domain of the heterodimeric receptor complex then couples with a specific G protein alpha subunit, G alpha gustducin, resulting in downstream effector signals including increased intracellular calcium.2 The activity of G alpha gustducin also leads to activation of transient receptor potential ion channel 5 (TRPM5), a cation channel whose downstream effects are not yet well understood.3

The discovery of G alpha gustducin expression in luminal gut epithelium raised the intriguing possibility that the gut is somehow able to “taste” luminal contents.4 More recently, taste receptors and their downstream effectors were shown to be expressed within the stomach, proximal …
Cardiac Responses to Isometric Exercise
Authors: VERONICA M. QUARRY, DAVID H. SPODICK
Journal: Circulation (1974)

The time course of cardiocirculatory responses to different levels of isometric handgrip (IHG) in sitting position were studied noninvasively in normal males and compared to supine IHG results in the same subjects. Control Comparisons. Resting postural differences were as expected: sitting heart rates (HR), pre-ejection phase (PEP) and PEP/LVET were higher while left ventricular ejection time (LVET) and ejection time index (ETI) were lower than those supine (P &lt; 0.05 to P &lt; 0.001). The following trends, while not statistically significant, were also noted: systolic and diastolic blood pressure were lower while pressure-rate product (PRP), the interval from appearance of the Q wave to the first major "mitral" component of the first heart sound (Q-I M ), and isovolumic contraction time (IVCT) tended to be higher than those supine. Isometric Exercise. The supine IHG results are consistent with data reported in the literature. During sitting IHG at 15% maximum voluntary contraction (MVC) there was no statistical change in any parameter measured. At 30%, 50%, and 100% MVC there were increases in HR, systolic and diastolic pressures, and PRP. At 30% MVC, Q-I M and pulse transmission time (PTT) decreased, ETI increased and IVCT, PEP, LVET, and PEP/LVET did not change significantly. At 50% MCV, Q-I M , IVCT, PEP, LVET, PEP/LVET and PTT shortened while ETI increased. At 100% MCV, Q-I M , IVCT, PEP, and LVET shortened but no significant changes occurred in PEP/LVET or ETI. When sitting IHG was compared to supine IHG the end points of exercise yielded statistically similar values for systolic and diastolic pressures, PRP, Q-I M , IVCT, PEP, and PTT. LVET and ETI were consistently lower ( P &lt; 0.02) while HR and PEP/LVET were higher for sitting vs supine IHG. Standard errors were smaller supine, a finding that indicates greater homogeneity of response in this posture and probably explains why some changes in cardiac parameters at lower levels of IHG reached statistical significance in the supine but not the sitting position. The changes in systolic intervals are consistent with the increased contractility resulting from IHG. Lack of uniform decreases in PEP/LVET with higher levels of IHG, however, were believed to reflect decreased myocardial adaptability to higher pressure (vs volume) loads. Decreases in pulse transmission time appeared to be influenced by diastolic pressure increases which were directly related to the levels of IHG. Once resting postural differences are accounted for, however, the effect of posture on IHG is not very great and certainly does not present the disparity which exists between sitting and supine rhythmic exercise. Most responses were directly related to the level of exertion, with greater changes occurring at the higher levels of IHG. For noninvasive studies, 50% or 100% MVC are the recommended levels of exertion since significant cardiocirculatory responses are greater than at 15% and 30% MVC and occur within one minute.
WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors
Authors: Lu Cui, Yuan Guan, Zepeng Qu, Jingfa Zhang, Bing Liao, Bo Ma, Jiang Qian, Dangsheng Li, Weiye Li, Guo-Tong Xu, Ying Jin
Journal: Journal of Clinical Investigation (2013)

Tumor formation constitutes a major obstacle to the clinical application of embryonic stem cell–derived (ESC-derived) cells. In an attempt to find major extracellular signaling and intrinsic factors controlling tumorigenicity and therapeutic functionality of transplanted ESC-derived retinal progenitor cells (ESC-RPCs), we evaluated multiple kinds of ESC-RPCs in a mouse retinal degeneration model and conducted genome-wide gene expression profiling. We identified canonical WNT signaling as a critical determinant for the tumorigenicity and therapeutic function of ESC-RPCs. The function of WNT signaling is primarily mediated by TCF7, which directly induces expression of Sox2 and Nestin. Inhibition of WNT signaling, overexpression of dominant-negative Tcf7, and silencing Tcf7, Sox2, or Nestin all resulted in drastically reduced tumor formation and substantially improved retinal integration and visual preservation in mice. These results demonstrate that the WNT signaling cascade plays a critical role in modulating the tumorigenicity and functionality of ESC-derived progenitors.
Diabetes and End-Stage Renal Disease Synergistically Contribute to Increased Incidence of Cardiovascular Events: A Nationwide Follow-up Study During 1998–2009
Authors: Yu-Tzu Chang, Jia-Ling Wu, Chih-Cheng Hsu, Jung-Der Wang, Junne-Ming Sung
Journal: Diabetes Care (2013)

OBJECTIVE This study aimed to investigate the effect of interaction of diabetes and end-stage renal disease (ESRD) on the risks of cardiovascular (CV) events. RESEARCH DESIGN AND METHODS By using two representative national cohorts, we determined the age- and sex-specific incidences and 20-year risks of incident CV events, including acute myocardial infarction (AMI), stroke, and congestive heart failure (CHF), stratified by the presence of diabetes, de novo diabetes after ESRD, or ESRD. Individuals were excluded if age <18 years or if previous CV events or malignancies were present before enrollment. Cox proportional hazards models were also constructed with adjustments for competing risk of mortality. RESULTS A total 648,851 non-ESRD individuals and 71,397 ESRD patients, including 53,342 and 34,754 diabetic patients, respectively, were followed up during 1998-2009. A monotonic risk pattern of CV-related incidences was noted with the presence of diabetes, ESRD, or both, respectively, after stratification by age and sex. De novo diabetes showed similar increased risks for CV incidences, especially AMI and stroke. There is a multiplicatively synergistic effect of diabetes and ESRD for CV-related risks, especially for AMI and stroke, of which the adjusted hazard ratios (aHRs) were 5.24 (95% CI 4.83-5.68) and 2.43 (2.32-2.55), respectively, in comparison with people without diabetes or ESRD; de novo diabetes after ESRD had similar effects with aHRs of 4.12 (3.49-4.87) and 1.75 (1.57-1.95), respectively. CONCLUSIONS Diabetes and ESRD synergistically increase risks of CV events. Proactive screening and control for diabetes in patients with ESRD should be built into our daily practice.
Hypopigmented mycosis fungoides in a light-skinned woman
Authors: None Moulonguet, None Robert, None Baudot, None Flageul, None Dubertret
Journal: British Journal of Dermatology (1998)

Journal Article Hypopigmented mycosis fungoides in a light‐skinned woman Get access I. Moulonguet, I. Moulonguet Department of Dermatology, Hôpital Saint‐Louis, Paris, France. Search for other works by this author on: Oxford Academic Google Scholar C. Robert, C. Robert Department of Dermatology, Hôpital Saint‐Louis, Paris, France. Search for other works by this author on: Oxford Academic Google Scholar N. Baudot, N. Baudot Department of Dermatology, Hôpital Saint‐Louis, Paris, France. Search for other works by this author on: Oxford Academic Google Scholar B. Flageul, B. Flageul Department of Dermatology, Hôpital Saint‐Louis, Paris, France. Search for other works by this author on: Oxford Academic Google Scholar L. Dubertret L. Dubertret Department of Dermatology, Hôpital Saint‐Louis, Paris, France. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 139, Issue 2, 1 August 1998, Pages 341–343, https://doi.org/10.1046/j.1365-2133.1998.02379.x Published: 01 August 1998
MENTAL CHANGES FOLLOWING THE REMOVAL OF THE RIGHT CEREBRAL HEMISPHERE FOR BRAIN TUMOR
Authors: Stuart N. Rowe
Journal: American Journal of Psychiatry (1937)

1. A case of removal of the right cerebral hemisphere for brain tumor is reported. 2. From a neurological standpoint, the return of considerable motor function and some sensory function on the opposite side of the body is of interest. 3. Mental changes including impairment of recent memory, emotional instability and diminution in the normal inhibitions, are present six months after the operation, but the patient's intellectual resources, personality and ability to meet the demands of her daily life have not been greatly altered. 4. The relatively mild mental changes resulting from hemispherectomy in this case are in keeping with previous experimental and clinical studies which indicate that in primates and man the higher cerebral functions are more severely altered by bilateral frontal lobe injury than by corresponding or even more extensive lesions of any other areas.
Comprehensive Characterization of <b> <i>Annexin I</i> </b> Alterations in Esophageal Squamous Cell Carcinoma
Authors: Nan Hu, Michael J. Flaig, Hua Su, Jian-Zhong Shou, Mark J. Roth, Wen-Jun Li, Chaoyu Wang, Alisa M. Goldstein, Guang Li, Michael R. Emmert-Buck, Philip R. Taylor
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to characterize alterations of the annexin I gene, its mRNA, and protein expression in esophageal squamous cell carcinoma. Experimental Design: Fifty-six cases of esophageal squamous cell carcinoma were analyzed using four microsatellite markers flanking the annexin I gene (9q11-q21) to identify loss of heterozygosity. In addition, we performed (a) single-strand conformation polymorphism and DNA sequencing along the entire promoter sequence and coding region to identify mutations, (b) real-time quantitative reverse transcription-PCR of RNA from frozen esophageal squamous cell carcinoma tissue (n = 37) and in situ hybridization (n = 5) on selected cases to assess mRNA expression, and (c) immunohistochemistry (n = 44) to evaluate protein expression. The prevalence of the allelic variants identified in the first 56 patients was refined in 80 additional esophageal squamous cell carcinoma patients and 232 healthy individuals. Results: Forty-six of 56 (82%) esophageal squamous cell carcinoma patients showed loss of an allele at one or more of the four microsatellite markers; however, only one (silent) mutation was seen. Two intragenic variants were identified with high frequency of allelic loss (A58G, 64%; L109L, 69%). Thirty of 37 (81%) esophageal squamous cell carcinoma patients showed reduced annexin I mRNA expression, which was confirmed by in situ hybridization, whereas annexin I protein expression was reduced in 79% of poorly differentiated tumor cell foci but in only 5% of well-differentiated tumor foci, although allelic loss on chromosome 9 was found in both tumor grades. Conclusions: Allelic loss of annexin I occurs frequently, whereas somatic mutations are rare, suggesting that annexin I is not inactivated in esophageal squamous cell carcinoma via a two-hit mechanism. A decrease in annexin I protein expression was confirmed, consistent with a quantitative decrease in mRNA expression, and appeared to be related to tumor cell differentiation. We conclude that annexin I is not the tumor suppressor gene corresponding to the high levels of loss of heterozygosity observed on chromosome 9 in esophageal squamous cell carcinoma; however, dysregulation of mRNA and protein levels is associated with this tumor type.
Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models.
Authors: W Kuang, H Xu, P H Vachon, L Liu, F Loechel, U M Wewer, E Engvall
Journal: Journal of Clinical Investigation (1998)

Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter in mice with complete or partial deficiency of merosin. The transgene restores the synthesis and localization of merosin in skeletal muscle, and greatly improves muscle morphology and integrity and the health and longevity of the mice. However, the transgenic mice share with the nontransgenic dystrophic mice a progressive lameness of hind legs, suggestive of a nerve defect. These results indicate that the absence of merosin in tissues other than the muscle, such as nervous tissue, is a critical component of MCMD. Future gene therapies of human MCMD, and perhaps of other forms of muscular dystrophy, may require restoration of the defective gene product in multiple tissues.
Ecological Nitrogen Limitation Shapes the DNA Composition of Plant Genomes
Authors: C. Acquisti, J. J. Elser, S. Kumar
Journal: Molecular Biology and Evolution (2009)

Phenotypes and behaviors respond to resource constraints via adaptation, but the influence of ecological limitations on the composition of eukaryotic genomes is still unclear. We trace connections between plant ecology and genomes through their elemental composition. Inorganic sources of nitrogen (N) are severely limiting to plants in natural ecosystems. This constraint would favor the use of N-poor nucleotides in plant genomes. We show that the transcribed segments of undomesticated plant genomes are the most N poor, with genomes and proteomes bearing signatures of N limitation. Consistent with the predictions of natural selection for N conservation, the precursors of transcriptome show the greatest deviations from Chargaff's second parity rule. Furthermore, crops show higher N contents than undomesticated plants, likely due to the relaxation of natural selection owing to the use of N-rich fertilizers. These findings indicate a fundamental role of N limitation in the evolution of plant genomes, and they link the genomes with the ecosystem context within which biota evolve.
The diagnostic value of perivascular infiltrates in muscle biopsy specimens for the assessment of rheumatoid vasculitis
Authors: A. E Voskuyl, S. G van Duinen, A. H Zwinderman, F. C Breedveld, J. M W Hazes
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To determine the diagnostic value of perivascular infiltrates (PVI) in randomly obtained muscle biopsy specimens for the assessment of rheumatoid vasculitis (RV). <h3>METHODS</h3> The number and size of PVIs, defined as the presence of mononuclear or polymorphonuclear cells around ⩾ 50% of the circumference of a vessel wall, as well as the presence of fibrinoid necrosis were determined in frozen sections of muscle samples of RV patients with histologically confirmed vasculitis in fixed muscle tissue (n=12). The findings were compared with those observed in frozen sections of muscle biopsy specimens of rheumatoid arthritis (RA) patients not suspected of vasculitis (n=14) and patients with osteoarthritis (OA) (n=11). The presence of PVIs and of fibrinoid necrosis were sought in four frozen sections of the muscle biopsy specimen. <h3>RESULTS</h3> PVIs were observed in 75% of the RV patients, which was significantly (p &lt; 0.05) higher than the frequency found in RA (14%) or OA (18%) patients. PVIs with ⩾ three cell layers were found in 67% of the RV patients and in none of the RA and OA patients (p &lt; 0.05). Fibrinoid necrosis was found in least one of four frozen section in 33% of the RV patients. There was a good intra-observer and inter-observer concordance on the presence of fibrinoid necrosis and of PVIs with ⩾ three cell layers. <h3>CONCLUSIONS</h3> The assessment of PVIs with ⩾ three cell layers in a muscle biopsy specimen is a specific and reliable test in discriminating RV from RA without vasculitis. The demonstration in muscle of PVIs with ⩾ three cell layers is more sensitive than that of fibrinoid necrosis in the diagnosis of RV.
The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart
Authors: T BRADE, J MANNER, M KUHL
Journal: Cardiovascular Research (2006)

The heart is one of the first organs to function in the developing embryo. Vertebrate heart development can be subdivided into different phases, e.g. specification of myo- and endocardial progenitor cells during the establishment of heart-forming fields within the anterior lateral plate mesoderm, formation of the linear heart tube by merging of the paired heart-forming fields in front of the foregut, looping of the heart tube and transformation of the tubular embryonic heart into the four-chambered heart. The molecular mechanisms underlying these processes are phylogenetically remarkably conserved and involve the activation of specific transcriptional programs by different extracellular growth factors. In this review, we will focus on the functions of the Wnt family of growth factors in normal cardiac development and in tissue remodelling in the mature heart under pathological conditions.
Comparison of Adrenergic Mechanisms in an Elastic and a Muscular Artery of the Rabbit
Authors: J. A. BEVAN, R. D. BEVAN, R. E. PURDY, C. P. ROBINSON, C. SU, J. G. WATERSON
Journal: Circulation Research (1972)

Elastic and muscular arteries are known to differ in function and in the magnitude of their response to vasoconstrictor influences. With the isolated thoracic aorta and ear artery of the rabbit as representative arteries, the morphological, physiological, and pharmacological correlates of these differences have been sought among their presynaptic adrenergic mechanisms. The adrenergic nerve plexus in the ear artery is wider and the nodes are denser than they are in the aorta. There is some evidence consistent with the hypothesis that the thicker the plexus, the greater the reuptake of released transmitter, the smaller the transmitter overflow, and the lower the efficiency of uptake of exogenous norepinephrine. Measurements of fractional release of tritiated norepinephrine suggest that qualitative differences in the adrenergic transmitter storage and release mechanisms may exist between the two vessels. Thus the considerable functional difference between the two vessels is in part, at any rate, a consequence of adrenergic mechanisms which differ both quantitatively and qualitatively from each other.
Posterior shear force and posterior tibial displacement using a sling bridge in patients with posterior cruciate ligament insufficiency
Authors: T Sakai, M Koyanagi, K Nakata, H Fujisaki, T Yamagata, K Hidaka, Y Suzuki, N Nakamura
Journal: British Journal of Sports Medicine (2011)

Background Rehabilitation training of hamstring muscle with deep knee flexion should be restricted following the posterior cruciate ligament (PCL) reconstruction because it stresses the PCL graft. To perform rehabilitation training of the hamstring muscle without the stress to the PCL, we have developed a sling bridge exercise (SB), which is a hamstring exercise with a sling at a lower leg to lift the buttocks in a supine position. Our hypothesis is that anterior traction force generated by a sling decrease strain on the PCL during SB. Objective To analyze posterior shear force and amount of posterior tibial displacement by the SB and compare with those by the conventional bridge (CB) exercise. Design Quasi-experimental study. Setting Controlled laboratory research. Participants Five healthy male volunteers and one patient with PCL insufficiency. Intervention Position of physical segments and force on floor were analyzed by a 3D motion capture system and force plate. Posterior tibial displacement was measured by lateral XP view of the knee during the exercises. Main outcome measurements Posterior shear force of the knee was calculated by using a biomechanical musculoskeletal model. Posterior tibial displacement was measured by digitised XP. Results Posterior shear force of the healthy volunteers was 849.0 ± 322.5 N during CB and 360.6 ± 75.5 N during SB. In a patient with the PCL insufficiency, side-to side difference in posterior tibial displacement by SB (1.2 mm) was smaller than that of CB (3.3 mm). Conclusion The SB hamstring exercise causes less posterior shear force and resulted in less posterior tibial displacement than a CB exercise. Therefore, a sling hamstring exercise is safer than a CB exercise in rehabilitation training for the patients with PCL reconstruction of the knee.
Sociopathic Personality in Identical Twins in a Set of Dizygotic Triplets
Authors: THOMAS L. TRUNNELL
Journal: American Journal of Psychiatry (1967)

The manifestation of sociopathic personality in identical twins who are members of a dizygotic set of triplets is reported; the third triplet showed no evidence of personality disturbance. The author suggests that environmental and psychodynamic factors had an essential role in the development of the sociopathic personality disturbances.