tbuckley/cabot-search huggingface dataset:
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients
Authors: Sadudee Chotirat, Wanna Thongnoppakhun, Orathai Promsuwicha, Chetsada Boonthimat, Chirayu U Auewarakul
Journal: Journal of Hematology & Oncology (2012)

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases.Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored.The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed.Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
Risk of Advanced Proximal Neoplasms According to Distal Colorectal Findings: Comparison of Sigmoidoscopy-Based Strategies
Authors: Antoni Castells, Xavier Bessa, Enrique Quintero, Luis Bujanda, Joaquín Cubiella, Dolores Salas, Ángel Lanas, Fernando Carballo, Juan Diego Morillas, Cristina Hernández, Rodrigo Jover, Isabel Montalvo, Juan Arenas, Ángel Cosme, Vicent Hernández, Begoña Iglesias, Inés Castro, Lucía Cid, Teresa Sala, Marta Ponce, Mercedes Andrés, Gloria Teruel, Antonio Peris, María-Pilar Roncales, Francisca González-Rubio, Agustín Seoane-Urgorri, Jaume Grau, Anna Serradesanferm, Maria Pellisé, Akiko Ono, José Cruzado, Francisco Pérez-Riquelme, Inmaculada Alonso-Abreu, Marta Carrillo-Palau, Mariola de la Vega-Prieto, Rosario Iglesias, Javier Amador, José Manuel Blanco, Rocío Sastre, Juan Ferrándiz, Mª José González-Hernández, Montserrat Andreu
Journal: JNCI Journal of the National Cancer Institute (2013)

Screening for colorectal cancer with sigmoidoscopy benefits from the fact that distal findings predict the risk of advanced proximal neoplasms (APNs). This study was aimed at comparing the existing strategies of postsigmoidoscopy referral to colonoscopy in terms of accuracy and resources needed. Asymptomatic individuals aged 50–69 years were eligible for a randomized controlled trial designed to compare colonoscopy and fecal immunochemical test. Sigmoidoscopy yield was estimated from results obtained in the colonoscopy arm according to three sets of criteria of colonoscopy referral (from those proposed in the UK Flexible Sigmoidoscopy, Screening for COlon REctum [SCORE], and Norwegian Colorectal Cancer Prevention [NORCCAP] trials). Advanced neoplasm detection rate, sensitivity, specificity, and number of individuals needed to refer for colonoscopy to detect one APN were calculated. Logistic regression analysis was performed to identify distal findings associated with APN. All statistical tests were two-sided. APN was found in 255 of 5059 (5.0%) individuals. Fulfillment of UK (6.2%), SCORE (12.0%), and NORCCAP (17.9%) criteria varied statistically significantly (P < .001). The NORCCAP strategy obtained the highest sensitivity for APN detection (36.9%), and the UK approach reached the highest specificity (94.6%). The number of individuals needed to refer for colonoscopy to detect one APN was 6 (95% confidence interval [CI] = 4 to 7), 8 (95% CI = 6 to 9), and 10 (95% CI = 8 to 12) when the UK, SCORE, and NORCCAP criteria were used, respectively. The logistic regression analysis identified distal adenoma ≥10mm (odds ratio = 3.77; 95% CI = 2.52 to 5.65) as the strongest independent predictor of APN. Whereas the NORCCAP criteria achieved the highest sensitivity for APN detection, the UK recommendations benefited from the lowest number of individuals needed to refer for colonoscopy.
Basic Advances and New Avenues in Therapy of Spinal Cord Injury
Authors: Bruce H. Dobkin, Leif A. Havton
Journal: Annual Review of Medicine (2004)

The prospects for successful clinical trials of neuroprotective and neurorestorative interventions for patients with acute and chronic myelopathies depend on preclinical animal models of injury and repair that reflect the human condition. Remarkable progress continues in the attempt to promote connections between the brain and the sensory and motor neurons below a spinal cord lesion. Recent experiments demonstrate the potential for biological therapies to regenerate or remyelinate axons and to incorporate new neural cells into the milieu of a traumatic spinal cord injury. The computational flexibility and plasticity of the sensorimotor systems of the brain, spinal cord, and motor unit make functional use of new circuitry feasible in patients. To incorporate residual and new pathways, neural repair strategies must be coupled to rehabilitation therapies that drive activity-dependent plasticity for walking, for reaching and grasping, and for bowel and bladder control. Prevention of pain and dysautonomia are also clinical targets. Research aims to define the temporal windows of opportunity for interventions, test the safety and efficacy of delivery systems of agents and cells, and provide a better understanding of the cascades of gene expression and cell interactions both acutely and chronically after injury. These bench-to-bedside studies are defining the neurobiology of spinal cord injury rehabilitation.
A genetic association study between asthma and CD14 promoter polymorphism in Chinese children
Authors: T.F. Leung, N.L.S. Tang, Y.M. Sung, G.W.K. Wong, C.W.K. Lam, A.M. Li, I.H.S. Chan, T.F. Fok
Journal: Journal of Allergy and Clinical Immunology (2003)
Impaired Nuclear Translocation of the Glucocorticoid Receptor in Corticosteroid-Insensitive Airway Smooth Muscle in Severe Asthma
Authors: Po-Jui Chang, Charalambos Michaeloudes, Jie Zhu, Nooreen Shaikh, Josephine Baker, Kian Fan Chung, Pankaj K. Bhavsar
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA.
Evaluation of Factors Affecting Awareness of and Willingness to Participate in Cancer Clinical Trials
Authors: Primo N. Lara, Debora A. Paterniti, Christine Chiechi, Corinne Turrell, Claudia Morain, Nora Horan, Lisa Montell, Jose Gonzalez, Sharon Davis, Ari Umutyan, Cynthia L. Martel, David R. Gandara, Ted Wun, Laurel A. Beckett, Moon S. Chen
Journal: Journal of Clinical Oncology (2005)

Annually, only 3% of patients participate in cancer clinical trials (CCTs). Barriers to accrual include lack of CCT awareness and uncertain third-party payer coverage. In January 2002, a California law (Senate Bill 37 [SB37]) required all third-party payers to reimburse patient care costs related to CCTs. We evaluated the level of awareness of patients and/or their family members/friends regarding CCTs and SB37.We used both a written survey for patients and/or their family members and friends seen in oncology clinics, and a verbal telephone version for Cancer Information Service callers. We tested for correlations between CCT awareness and SB37 knowledge, and willingness to participate in CCTs.Of 1,188 respondents, 59% were aware of CCTs, 19% knew of SB37, and 36% were very likely to consider a CCT. There were significant positive correlations between CCT awareness and willingness to participate (P < .001, Spearman), and between SB37 knowledge and willingness to participate (P = .001, Pearson chi2). Reduced awareness was seen in respondents who were either black or African American (odds ratio [OR], 0.44; P = .004), Hispanic (OR, 0.56; P = .03), had an annual income less than 25,000 dollars (OR, 0.38; P < .001), or had less than a college degree (OR, 0.12 to 0.53; P < .001 to .013). Reduced willingness to participate in CCTs was seen in black or African American participants (OR, 0.38; P < .001), Asians (OR, 0.44; P < .006), or respondents aged 18 to 24 years (OR, 0.35; P = .002).These results support the hypothesis that improving CCT awareness and SB37 knowledge especially among lower income, less educated, and minority patients, may potentially overcome barriers to participation and subsequently increase accrual in California.
Preclinical Characterization of AEG35156/GEM 640, a Second-Generation Antisense Oligonucleotide Targeting X-Linked Inhibitor of Apoptosis
Authors: Eric C. LaCasse, Gabriele G. Cherton-Horvat, Kimberley E. Hewitt, Lori J. Jerome, Stephen J. Morris, Ekambar R. Kandimalla, Dong Yu, Hui Wang, Wei Wang, Ruiwen Zhang, Sudhir Agrawal, John W. Gillard, Jon P. Durkin
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics. Experimental Design: AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy. Results: AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by &amp;gt;80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels. Conclusions: AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia.
Acupuncture treatment in irritable bowel syndrome
Authors: A Schneider
Journal: Gut (2005)

Despite occasional positive reports on the efficacy of acupuncture (AC) on functions of the gastrointestinal tract, there is no conclusive evidence that AC is effective in the treatment of irritable bowel syndrome (IBS).Forty three patients with IBS according to the Rome II criteria were randomly assigned to receive either AC (n = 22) or sham acupuncture (SAC) (n = 21) using the so-called "Streitberger needle". Treatment duration was 10 sessions with an average of two AC sessions per week. The primary end point was improvement in quality of life (QOL) using the functional digestive diseases quality of life questionnaire (FDDQL) and a general quality of life questionnaire (SF-36), compared with baseline assessments. QOL measurements were repeated three months after treatment.Both the AC and SAC groups improved significantly in global QOL, as assessed by the FDDQL, at the end of treatment (p = 0.022), with no differences between the groups. SF-36 was insensitive to these changes (except for pain). This effect was partially reversed three months later. Post hoc comparison of responders and non-responders in both groups combined revealed a significant prediction of the placebo response by two subscales of the FDDQL (sleep, coping) (F = 6.746, p = 0.003) in a stepwise regression model.Acupuncture in IBS is primarily a placebo response. Based on the small differences found between the AC and SAC groups, a study including 566 patients would be necessary to prove the efficacy of AC over SAC. The placebo response may be predicted by high coping capacity and low sleep quality in individual patients.
Study of Montelukast for the Treatment of Respiratory Symptoms of Post–Respiratory Syncytial Virus Bronchiolitis in Children
Authors: Hans Bisgaard, Alejandro Flores-Nunez, Anne Goh, Parvin Azimi, Andrew Halkas, Marie-Pierre Malice, Jean-Louis Marchal, S Balachandra Dass, Theodore F Reiss, Barbara A Knorr
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: A pilot study (Bisgaard H; Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379–383) reported the efficacy of montelukast in post–respiratory syncytial virus (RSV) bronchiolitic respiratory symptoms.Objectives: To evaluate the efficacy and safety of montelukast, 4 and 8 mg, in treating recurrent respiratory symptoms of post-RSV bronchiolitis in children in a large, multicenter study.Methods: This was a double-blind study of 3- to 24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis and who tested positive for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was percentage symptom-free days (%SFD; day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough).Measurements and Main Results: No significant differences were seen between montelukast and placebo in %SFD over period I: mean ± SD for placebo and for montelukast at 4 and 8 mg were 37.0 ± 30.7, 38.6 ± 30.4, and 38.5 ± 29.9, respectively. Least-squares mean differences (95% confidence interval) between montelukast (4 mg) and placebo and between montelukast (8 mg) and placebo were 1.9% (−2.9, 6.7) and 1.6% (−3.2, 6.5), respectively. Secondary end points were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was approximately 29%. In post hoc analyses of patients (n = 523) with persistent symptoms (%SFD ≤ 30% over Weeks 1–2), differences in %SFD were seen between montelukast and placebo over Weeks 3–24: difference were 5.7 (0.0, 11.3) for montelukast (4 mg) minus placebo and 5.9 (0.1, 11.7) for montelukast (8 mg) minus placebo.Conclusions: In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.Clinical trial registered with www.clinicaltrials.gov (NCT00076973).
On Oxygen as a Therapeutic Agent
Authors: S. B. Birch
Journal: BMJ (1859)

<h3>Objective:</h3> To report the second patient with an autosomal recessive spinocerebellar ataxia 16 (SCAR16) associated with cervical dystonia, expand the phenotype of this rare condition and present the comprehensive phenotypic summary of all known carriers to date. Videos are available <h3>Background:</h3> A combination of dysarthria, ataxia and dystonia in one patient has a wide differential. Obtaining a diagnosis is often a challenging, laborious, but rewarding process. Subacute-onset cerebellar ataxia affecting siblings and skipping generations is suggestive of an autosomal-recessive hereditary ataxia, including Fredreich’s ataxia, ataxia teleangiectasia, ataxia with oculomotor apraxia and SCAR. SCAR 16 is a rare condition described in a handful of families worldwide. It is caused by a homozygous/compound heterozygous mutation in <i>STUB1</i>gene. <h3>Design/Methods:</h3> We describe a 45-year-old right-handed woman with a 6-month history of progressive speech and balance problems. Main features on examination were cervical dystonia, ataxia and dysarthria. Her 47-year old estranged sister had dysarthria and cognitive problems (declined the assessment). MRI brain (proband) showed severe cerebellar atrophy. Multiple laboratory and genetic tests were negative.Exome sequencing results were suggestive of SCAR16. Two compound heterozygous variants in <i>STUB1</i>gene were detected (1 novel). TOPOcloning showed variants to be in “trans” suggesting the pathogenicity. <h3>Results:</h3> Mutations in <i>STUB1</i>gene were first described in 2013 and may cause a spectrum of disorders involving ataxia and dysarthria, including: SCAR16, Gordon-Holmes syndrome and SCAR48. To date SCAR16 was described only in 11 families worldwide.The phenotype usually consists of:cognitive impairment, cerebellar and pyramidal signs and hormonal problems. Our patient is the second patient with dystonia reported to date. Moreover the families reported are of Asian origin, with three families from Saudi Arabia, Germany and Turkey.Our patient is the only other individual with European descent. <h3>Conclusions:</h3> We expand SCAR16 genotype and phenotype (the second report of dystonia, novel variant) and provide a comprehensive overview of all described cases to date. <b>Disclosure:</b> Dr. Olszewska has nothing to disclose. Dr. O’Riordan has nothing to disclose. Dr. Kinsella has nothing to disclose.
Epigenetic mechanisms in diabetic vascular complications
Authors: M. A. Reddy, R. Natarajan
Journal: Cardiovascular Research (2011)

There has been a rapid increase in the incidence of diabetes as well the associated vascular complications. Both genetic and environmental factors have been implicated in these pathologies. Increasing evidence suggests that epigenetic factors play a key role in the complex interplay between genes and the environment. Actions of major pathological mediators of diabetes and its complications such as hyperglycaemia, oxidant stress, and inflammatory factors can lead to dysregulated epigenetic mechanisms that affect chromatin structure and gene expression. Furthermore, persistence of this altered state of the epigenome may be the underlying mechanism contributing to a 'metabolic memory' that results in chronic inflammation and vascular dysfunction in diabetes even after achieving glycaemic control. Further examination of epigenetic mechanisms by also taking advantage of recently developed next-generation sequencing technologies can provide novel insights into the pathology of diabetes and its complications and lead to the discovery of much needed new drug targets for these diseases. In this review, we highlight the role of epigenetics in diabetes and its vascular complications, and recent technological advances that have significantly accelerated the field.
Tenascin-C synthesized in both donor grafts and recipients accelerates artery graft stenosis
Authors: Y SAWADA, K ONODA, K IMANAKAYOSHIDA, J MARUYAMA, K YAMAMOTO, T YOSHIDA, H SHIMPO
Journal: Cardiovascular Research (2007)

Tenascin-C, an extracellular matrix glycoprotein, is thought to play an important role in neointimal hyperplasia of artery bypass grafts. In this study, the direct contribution of tenascin-C to neointimal hyperplasia of free artery grafts and the origin of tenascin-C-producing cells were examined using tenascin-C transgenic mice.Abdominal aorta-to-carotid artery interposition grafting was performed in mice. When grafts from wild-type mice were transplanted to wild-type, neointimal hyperplasia was observed in the grafts at days 14 and 28. Immunohistochemical staining showed strong expression of tenascin-C in the media and neointima of the grafts. Much less neointimal hyperplasia was seen when grafts from tenascin-C-deficient mice were transplanted to tenascin-C-deficient mice. In tenascin-C-deficient grafts transplanted to wild-type mice, tenascin-C deposition was observed only in the neointima. In the reverse combination, deposition was seen in the media and neointima. The source of the tenascin-C-producing cells was analyzed using heterozygous mice that identically express both tenascin-C and LacZ. While LacZ-positive cells were seen only in the neointima of artery grafts from wild-type transplanted to mutant mice, positive cells were detected in both the neointima and media in grafts from mutant to wild-type mice.We presented direct evidence that tenascin-C is a crucial molecule in neointimal hyperplasia in free artery grafts, and that tenascin-C-producing cells are derived from both donor grafts and recipients.
Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature
Authors: J. Gieffers, G. van Zandbergen, J. Rupp, F. Sayk, S. Krüger, S. Ehlers, W. Solbach, M. Maass
Journal: European Respiratory Journal (2004)

Chlamydia pneumoniae , a major cause of community-acquired pneumonia, primarily infects the respiratory tract. Chronic infection of nonrespiratory sites, such as the vascular wall, the brain or blood monocytes, requires evasion from the lungs and spreading via the bloodstream. The cell types involved in dissemination are insufficiently characterised. In this study, New Zealand White rabbits were infected intratracheally with C. pneumoniae , and lung manifestation and systemic dissemination were monitored by polymerase chain reaction and immunohistochemistry. Infection of the lungs was characterised by an early phase dominated by granulocytes and a late phase dominated by alveolar macrophages (AM). Granulocytes, AM and alveolar epithelial cells acted as host cells for chlamydiae, which remained detectable for up to 8 weeks. AM transported the pathogen to the peribronchiolar lymphatic tissue, and subsequently C. pneumoniae entered the spleen and the aorta via dissemination by peripheral blood monocytes. In conclusion, Chlamydia pneumoniae -infected alveolar macrophages transmigrate through the mucosal barrier, and give the pathogen access to the lymphatic system and the systemic circulation. Infected peripheral blood monocytes are the vector system within the bloodstream and transmit the infection to the vascular wall. This is the first description of granulocytes acting as a reservoir for Chlamydia pneumoniae early in infection.
Penetrating wounds of the heart and great vessels: A report of 30 patients
Authors: C. E. Anagnostopoulos, C. F. Kittle
Journal: Thorax (1973)

In this series of 30 consecutively operated patients, two were probably dead from their cardiac wounds on arrival at hospital and two suffered extrapericardial large vessel injury. These four patients died. Among the remaining 26 patients who arrived alive in the emergency room with intrapericardial wounds, 23 (89%) survived during the four-and-a-half years covered by this report. These included five survivors in a subgroup of six patients with serious left ventricular wounds. The use of initial pericardiocentesis in 13, sternotomy in 10, and extracorporeal circulation in 7 of these 30 patients is emphasized.