tbuckley/cabot-search huggingface dataset:
MRI Volumes of the Hippocampus and Amygdala in Adults With Down’s Syndrome With and Without Dementia
Authors: Elizabeth H. Aylward, Qiang Li, Nancy A. Honeycutt, Andrew C. Warren, Margaret B. Pulsifer, Patrick E. Barta, Michael D. Chan, Paige D. Smith, Matthew Jerram, Godfrey D. Pearlson
Journal: American Journal of Psychiatry (1999)

This study sought to determine whether volumes of the hippocampus and amygdala are disproportionately smaller in subjects with Down's syndrome than in normal comparison subjects and whether volume reduction is greater in Down's syndrome subjects with dementia.The subjects were 25 adults with Down's syndrome (eight with dementia) and 25 cognitively normal adults who were individually matched on age, sex, and race. Magnetic resonance imaging measures included volumes of the hippocampus, amygdala, and total brain. Nineteen of the Down's syndrome subjects had follow-up scans (interscan interval = 9-41 months).Nondemented Down's syndrome subjects had significantly smaller volumes of the hippocampus, but not the amygdala, than their comparison subjects, even when total brain volume was controlled for. Volumes of both the hippocampus and the amygdala were smaller in the demented Down's syndrome subjects than in their comparison subjects, even when total brain volume was controlled for. Age was not correlated with volume of the hippocampus or amygdala among the nondemented Down's syndrome subjects and the comparison subjects; age was correlated with volume of the amygdala, but not the hippocampus, among the Down's syndrome subjects with dementia. Changes in volume over time were not statistically significant for either the demented or the nondemented subjects.Hippocampal volume, while disproportionately small for brain size in individuals with Down's syndrome, remains fairly constant through the fifth decade of life in those without dementia. All subjects over age 50 who had Down's syndrome demonstrated volume reduction in the hippocampus as well as clinical signs of dementia. Dementia was also associated with volume reductions in the amygdala that exceeded reductions in total brain volume.
RHOA-FAK Is a Required Signaling Axis for the Maintenance of KRAS-Driven Lung Adenocarcinomas
Authors: Georgia Konstantinidou, Giorgio Ramadori, Francesca Torti, Kim Kangasniemi, Rachel E. Ramirez, Yiran Cai, Carmen Behrens, Michael T. Dellinger, Rolf A. Brekken, Ignacio I. Wistuba, Adriana Heguy, Julie Teruya-Feldstein, Pier Paolo Scaglioni
Journal: Cancer Discovery (2013)

Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes.
Myocardial Strain Analysis in Acute Coronary Occlusion
Authors: Erik Lyseggen, Helge Skulstad, Thomas Helle-Valle, Trond Vartdal, Stig Urheim, Stein Inge Rabben, Anders Opdahl, Halfdan Ihlen, Otto A. Smiseth
Journal: Circulation (2005)

Background— This study proposes 2 new echocardiographic indices with potential application in acute coronary artery occlusion to differentiate between viable and necrotic myocardium and to identify reperfusion. We investigated whether the ratio between systolic lengthening and combined late and postsystolic shortening (L-S ratio) could identify viable myocardium and whether systolic myocardial compliance, calculated as systolic lengthening divided by systolic pressure rise, could identify necrotic myocardium. Methods and Results— In anesthetized dogs, we measured left ventricular (LV) pressure and long-axis strain by Doppler echocardiography (SDE) and sonomicrometry. The left anterior descending coronary artery was occluded for 15 minutes with 3-hour reperfusion (n=6), for 4 hours with 3-hour reperfusion (n=6), or for 4 hours with no reperfusion (n=6). Myocardial work was quantified by pressure–segment length analysis, necrosis by triphenyltetrazolium chloride staining, and edema by water content. L-S ratio and systolic compliance were calculated by SDE. The L-S ratio ranged between 0.00 and 1.00 and was well correlated with regional myocardial work ( r =0.77, P &lt;0.0001). In entirely passive myocardium, the L-S ratio approached 1 and was similar in viable (0.88±0.02) and necrotic (0.81±0.03) myocardium. Compliance, however, was reduced in necrotic myocardium owing to edema (0.07±0.01%/mm Hg) but was preserved in viable myocardium (0.15±0.01%/mm Hg, P &lt;0.05). Reperfusion of viable myocardium caused a reduction of the L-S ratio after 15 minutes (0.57±0.06, P &lt;0.05), reflecting recovery of function. Reperfusion of necrotic myocardium caused no change in the L-S ratio, but compliance was further reduced within 15 minutes (0.03±0.01%/mm Hg, P &lt;0.05). Conclusion— Myocardial L-S ratio and compliance by SDE identified active contraction and necrosis, respectively. These indices should be tested clinically for assessment of myocardial viability and reperfusion.
A controlled trial of antihypertensive therapy in systemic sclerosis (scleroderma).
Authors: J F Fries, C Wasner, J Brown, P Feigenbaum
Journal: Annals of the Rheumatic Diseases (1984)

Antihypertensive treatment may be life saving in scleroderma renal crisis. Patients surviving such crises frequently have had dramatic improvement in the dermal manifestations of their scleroderma. To investigate the potential role of antihypertensive treatment in nonhypertensive patients we randomly assigned 28 patients with systemic sclerosis into drug (14) and placebo (14) groups, using blocked randomisation , and followed them up in a prospective, double-blind clinical trial for 24 months. Overall, both groups improved slightly, with both subjective and objective markers. There were no statistically significant differences and no clinically meaningful trends between the 2 groups, except that the blood pressure was reduced in the group on the active drug.
High prevalence of mollusc shell hypersensitivity pneumonitis in nacre factory workers
Authors: R Orriols, JL Aliaga, JM Anto, A Ferrer, A Hernandez, MJ Rodrigo, F Morell
Journal: European Respiratory Journal (1997)

Following the discovery of hypersensitivity pneumonitis caused by the inhalation of mollusc shell dust in two workers from a nacre-button factory, the health status of 26 workers employed in sawing mollusc shells was investigated. The evaluation included the administration of two questionnaires and radiological, functional and immunological assessments of all workers at the outset and 1 year later, when hygienic and therapeutic measures had been taken. Six workers, in whom specific inhalation challenge test was positive, were diagnosed with mollusc shell hypersensitivity pneumonitis, thus yielding a prevalence of 23%. Evidence of diffuse lung disease and systemic symptoms was found in these patients. Nonspecific bronchial hyperreactivity was also found more frequently in patients with mollusc shell hypersensitivity pneumonitis. Specific immunoglobulin G (IgG) level and specific skin testing failed to differentiate patients with mollusc shell hypersensitivity pneumonitis from other exposed workers; whereas, nonspecific skin testing, which was impaired in the patients, did differentiate. Bronchoalveolar lavage and transbronchial biopsy performed in patients with mollusc shell hypersensitivity pneumonitis were consistent with the disease. Removal from an environment containing mollusc shell dust was followed by regression of clinical, radiological and functional changes. The clinical picture of the 20 workers who did not present mollusc shell hypersensitivity pneumonitis remained unchanged, but functional decline was observed despite improvement in the environmental conditions of the factory. This report describes the first series of patients with mollusc shell hypersensitivity pneumonitis studied, and underlines the importance of careful follow-up of workers occupationally-exposed to mollusc shell dust.
S6 Kinase 2 Promotes Breast Cancer Cell Survival via Akt
Authors: Savitha Sridharan, Alakananda Basu
Journal: Cancer Research (2011)

The 40S ribosomal protein S6 kinase (S6K) acts downstream of mTOR, which plays important roles in cell proliferation, protein translation, and cell survival and is a target for cancer therapy. mTOR inhibitors are, however, of limited success. Although Akt is believed to act upstream of mTOR, persistent inhibition of p70 S6 kinase or S6K1 can activate Akt via a negative feedback loop. S6K exists as two homologues, S6K1 and S6K2, but little is known about the function of S6K2. In the present study, we have examined the effects of S6K2 on Akt activation and cell survival. Silencing of S6K1 caused a modest decrease, whereas knockdown of S6K2 caused a substantial increase in TNF-α and TRAIL (TNF-related apoptosis-inducing ligand)-mediated apoptosis. In contrast to S6K1, depletion of S6K2 by siRNA decreased basal and TNF-induced Akt phosphorylation. Ectopic expression of constitutively active Akt in MCF-7 cells restored cell survival in S6K2-depleted cells. We have previously shown that activation of Akt induces downregulation of Bid via p53. Knockdown of S6K2 caused an increase in p53, and downregulation of p53 by siRNA decreased Bid level. Silencing of Bid blunted the ability of S6K2 deficiency to enhance TNF-induced apoptosis. Taken together, our study shows that the two homologues of S6K have distinct effects on Akt activation and cell survival. Thus, targeting S6K2 may be an effective therapeutic strategy to treat cancers.
Unconscious habit systems in compulsive and impulsive disorders
Authors: Natalie L. Cuzen, Naomi A. Fineberg, Dan J. Stein
Journal: Behavioral and Brain Sciences (2014)

Abstract It may be useful to consider the application of Huang &amp; Bargh's (H&amp;B's) theory of unconscious motivational processes to psychopathology. In disorders of compulsivity and impulsivity, an unconscious habit system may play a key role in explaining ego-dystonic or self-destructive behaviour. H&amp;B's theory may provide some insights into understanding conditions such as obsessive-compulsive disorder (OCD) and drug addiction; however, additional work is needed to address the neurocircuitry and neurochemistry mediating their abnormal underlying motivational processes.
Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients
Authors: Andrew P. Garner, Joseph M. Gozgit, Rana Anjum, Sadanand Vodala, Alexa Schrock, Tianjun Zhou, Cesar Serrano, Grant Eilers, Meijun Zhu, Julia Ketzer, Scott Wardwell, Yaoyu Ning, Youngchul Song, Anna Kohlmann, Frank Wang, Tim Clackson, Michael C. Heinrich, Jonathan A. Fletcher, Sebastian Bauer, Victor M. Rivera
Journal: Clinical Cancer Research (2014)

Abstract Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib–KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. Results: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. Conclusion:Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST. Clin Cancer Res; 20(22); 5745–55. ©2014 AACR.
Bevacizumab-Induced Diffusion Restriction in Patients With Glioma: Tumor Progression or Surrogate Marker of Hypoxia?
Authors: Johannes Rieger, Oliver Bähr, Michael W. Ronellenfitsch, Joachim Steinbach, Elke Hattingen
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: Therapy with bevacizumab results in high response rates in patients with malignant glioma. However, the mechanisms of action of bevacizumab are poorly understood. Blood-brain barrier reconstitution and vascular normalization have been proposed as phenoma distinct from classical effects of antiangiogenic therapy (ie, induction of hypoxia). Refined magnetic resonance imaging may help to clarify this issue. We, therefore, read with great interest the case report recently presented by Gerstner et al in Journal of Clinical Oncology that described an area of restricted diffusion in a patient with malignant glioma treated with bevacizumab as analyzed by diffusion weighted imaging (DWI). The diffusion-restricted area was biopsied. Histology displayed diffuse tumor progression. Therefore, the authors conclude that diffusion-restricted areas in patients with glioma who are treated with antiangiogenic therapy could represent a special pattern of recurrent tumor. We agree with the authors that diffusion restriction occurs in patients treated with bevacizumab. In our recently published analysis, 18 patients treated with bevacizumab were prospectively analyzed for areas of diffusion restriction on DWI, and apparent diffusion coefficient maps were generated. We found that diffusion-restricted areas accompanied by a corresponding apparent diffusion coefficient decrease occurred in 13 patients (65%). Magnetic resonance imaging–based perfusion analysis performed in two patients showed reduction of regional cerebral blood flow and volume that corresponded with diffusion restriction during treatment with bevacizumab. In one patient, a diffusion-restricted area was biopsied, and histology demonstrated atypical necrosis. Furthermore, immunohistochemistry showed heavy nuclear staining for hypoxia inducible factor-1 . Thus, although we agree that increases in DWI might reflect tumor recurrence where dense cell packing occurs, such as in lymphoma, our analysis suggests that alternative causes for diffusion restriction exist. In our series, DWI restriction was common in patients whose diseases were responding to treatment. The atypical necrosis together with the hypoxia inducible factor-1 induction would be compatible with chronic hypoxia induced by prolonged antiangiogenic therapy. Whether antiangiogenic therapy truely induces hypoxia might be relevant given the therapy-resistant phenotype and diffuse infiltrating growth pattern often observed in gliomas after antiangiogenic therapy, as hypoxia might contribute to both phenoma.
Is Pain Intensity a Predictor of the Complexity of Cancer Pain Management?
Authors: Robin L. Fainsinger, Alysa Fairchild, Cheryl Nekolaichuk, Peter Lawlor, Sonya Lowe, John Hanson
Journal: Journal of Clinical Oncology (2008)

The lack of a standardized cancer pain (CP) classification system prompted the development of the Edmonton Classification System for Cancer Pain (ECS-CP). Its five features have demonstrated value in predicting pain management complexity. Pain intensity (PI) at initial assessment has been proposed as having additional predictive value. We hypothesized that patients with moderate to severe CP would take longer to achieve stable pain control, use higher opioid doses, and require more complicated analgesic regimens than would patients with mild CP at initial assessment.A secondary analysis of a multicenter ECS-CP validation study involving patients with advanced cancer was conducted (n = 591). Associations between PI and length of time to stable pain control (Cox regression), final opioid dose (Kruskal-Wallis one-way analysis of variance), and number of adjuvant modalities (chi(2)) were calculated. PI at initial assessment was defined using a numerical scale as mild (0 to 3), moderate (4 to 6), or severe (7 to 10).Patients with moderate and severe pain required a significantly longer time to achieve stable pain control (P < .0001). PI was a significant predictor of length of time to stable pain control in the univariate regression analysis. The four significant predictors in the multivariate model were moderate and severe PI (P < .0001), age (P = .001), and neuropathic pain (P = .002). Patients with moderate to severe pain required significantly higher final opioid doses (P < .0001) and more adjuvant modalities (P = .015).PI at initial assessment is a significant predictor of pain management complexity and length of time to stable pain control. Incorporation of this feature into the ECS-CP needs additional consideration.
Malignant melanoma metastases to the alimentary tract.
Authors: A Fraser-Moodie, R G Hughes, S M Jones, B A Shorey, L Snape
Journal: Gut (1976)

Seven patients are presented each with symptomatic malignant melanoma metastases to the alimentary tract. Where practicable, surgical excision of the metastases is justified because two patients have had worthwhile periods of survival.
The Challenge of Mild Traumatic Brain Injury: Role of Biochemical Markers in Diagnosis of Brain Damage
Authors: Stefania Mondello, Kara Schmid, Rachel P. Berger, Firas Kobeissy, Domenico Italiano, Andreas Jeromin, Ronal L. Hayes, Frank C. Tortella, Andras Buki
Journal: Medicinal Research Reviews (2013)

Abstract During the past decade there has been an increasing recognition of the incidence of mild traumatic brain injury (mTBI) and a better understanding of the subtle neurological and cognitive deficits that may result from it. A substantial, albeit suboptimal, effort has been made to define diagnostic criteria for mTBI and improve diagnostic accuracy. Thus, biomarkers that can accurately and objectively detect brain injury after mTBI and, ideally, aid in clinical management are needed. In this review, we discuss the current research on serum biomarkers for mTBI including their rationale and diagnostic performances. Sensitive and specific biomarkers reflecting brain injury can provide important information regarding TBI pathophysiology and serve as candidate markers for predicting abnormal computed tomography findings and/or the development of residual deficits in patients who sustain an mTBI. We also outline the roles of biomarkers in settings of specific interest including pediatric TBI, sports concussions and military injuries, and provide perspectives on the validation of such markers for use in the clinic. Finally, emerging proteomics‐based strategies for identifying novel markers will be discussed.
Postoperative Pain Assessment and Analgesic Administration in Native American Patients Undergoing Laparoscopic Cholecystectomy
Authors: Elizabeth Lee, Mary Teeple, Naina Bagrodia, Jack Hannallah, Nazhone P. Yazzie, William J. Adamas-Rappaport
Journal: JAMA Surgery (2013)

Ethnic disparities in pain assessment and analgesic administration following surgery have received little attention in the surgery literature. We noted that our Native American patients were less likely than others to complain of pain. A retrospective chart review of 21 Native American patients and a control group who underwent outpatient, elective laparoscopic cholecystectomy was performed. Native American patients had a statistically lower numeric pain score (mean, 6.5; 95% CI, 3.6-9.4) than non–Native American patients (mean, 8.1; 95% CI, 6.3-9.9; t<sub>38</sub> = 2.63; P &lt; .05). Native American patients also received less postsurgical analgesic (mean, 7.4; 95% CI, 4.0-10.8) than non–Native American patients (mean, 11.2; 95% CI, 7.2-15.2; t<sub>38</sub> = 3.07; P &lt; .01). Medical staff attending Native American patients should be aware that response to some scales to assess pain may not reflect accurately the degree of pain experienced.
Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma
Authors: Christophe Cellier, Eric Delabesse, Christine Helmer, Natacha Patey, Claude Matuchansky, Bana Jabri, Elizabeth Macintyre, Nadine Cerf-Bensussan, Nicole Brousse
Journal: The Lancet (2000)
MCP-1 overexpressed in tuberous sclerosis lesions acts as a paracrine factor for tumor development
Authors: Shaowei Li, Fumiko Takeuchi, Ji-an Wang, Christopher Fuller, Gustavo Pacheco-Rodriguez, Joel Moss, Thomas N. Darling
Journal: The Journal of Experimental Medicine (2005)

Patients with tuberous sclerosis complex (TSC) develop hamartomatous tumors showing loss of function of the tumor suppressor TSC1 (hamartin) or TSC2 (tuberin) and increased angiogenesis, fibrosis, and abundant mononuclear phagocytes. To identify soluble factors with potential roles in TSC tumorigenesis, we screened TSC skin tumor–derived cells for altered gene and protein expression. Fibroblast-like cells from 10 angiofibromas and five periungual fibromas produced higher levels of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein than did fibroblasts from the same patient's normal skin. Conditioned medium from angiofibroma cells stimulated chemotaxis of a human monocytic cell line to a greater extent than conditioned medium from TSC fibroblasts, an effect blocked by neutralizing MCP-1–specific antibody. Overexpression of MCP-1 seems to be caused by loss of tuberin function because Eker rat embryonic fibroblasts null for Tsc2 (EEF Tsc2−/−) produced 28 times as much MCP-1 protein as did EEF Tsc2+/+ cells; transient expression of WT but not mutant human TSC2 by EEF Tsc2−/− cells inhibited MCP-1 production; and pharmacological inhibition of the Rheb-mTOR pathway, which is hyperactivated after loss of TSC2, decreased MCP-1 production by EEF Tsc2−/− cells. Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target.