tbuckley/cabot-search huggingface dataset:
Leptomeningeal Metastases: Current Concepts and Management Guidelines
Authors: Sajeel Chowdhary, Marc Chamberlain
Journal: Journal of the National Comprehensive Cancer Network (2005)

Neoplastic infiltration of the meninges occurs when malignant cells gain entry into the cerebrospinal fluid (CSF). This is clinically recognized in 4% to 7% of all cancer patients. Leptomeningeal metastases may involve any part of the neural axis via tumor seeding; thus, a multitude of clinical presentations involving one or more domains exist, including the cerebral hemisphere, cranial nerves, and spinal cord and roots. The diagnosis of CSF metastases is often delayed and not appreciated until fixed neurologic deficits become evident. Adequate cytologic analysis of CSF fluid, neuroradiography of brain and spine, and an appropriate clinical context are the key element in diagnosing leptomeningeal metastases. A major challenge of treating neoplastic meningitis is the importance of treating the entire neural axis and stratifying patients in poor risk or good risk categories. Treatment is palliative and involves stabilizing neurologic status and prolonging survival. Median survival for untreated patients is 4 to 6 weeks. Treatment in a broad perspective entails radiotherapy and chemotherapy (systemic and intra-CSF). Commonly used intra-CSF chemotherapy regimens use drugs such as methotrexate, cytarabine, thiotepa, and a sustained-release liposome-encapsulated form of cytarabine (Depocyt, SkyePharma, London, UK). Patients with neoplastic meningitis usually experience a limited survival, even when treated using close adherence to evaluation algorithms and treatment protocols. In randomized controlled clinical trials using currently available intra-CSF chemotherapeutic agents, median survival in carefully selected, study-eligible groups of patients was 2 to 6 months.
Radiation Treatments After Breast-Conserving Therapy for Elderly Patients
Authors: Benjamin D. Smith, Thomas A. Buchholz
Journal: Journal of Clinical Oncology (2013)

Radiation treatments play an important role in the multidisciplinary management of most patients with breast cancer. Data from prospective phase III trials indicate that, for patients treated with a breast-conserving surgery, radiation reduces the risk of local recurrence, provides a clinically significant reduction in distant metastases, and improves overall survival. 1,2 Radiation treatments are also welltoleratedand,whendeliveredusingmoderntechnologies,carryalow risk of serious morbidity. However, there are also down sides to radiation treatments, most important of which are the inconvenience andcostsassociatedwithdailytreatmentsthatareadministeredovera 3- to 6-week period. Therefore, it would be ideal to identify favorable subgroups of patients treated with breast conservation for whom radiation could be avoided. In the past two decades, several randomized trials attempted to do this, but unfortunately most of these trials wereunsuccessfulatidentifyingagoodrisksubsetthatcouldbespared radiation. One notable exception was the Cancer and Leukemia GroupB(CALGB)9343trial,whichfoundthatpatientsolderthanage 70 with stage I, estrogen receptor (ER) ‐positive breast cancer who were treated with surgery and adjuvant tamoxifen without breast irradiation had a low 5-year local recurrence rate. In the article that accompanies this editorial, Hughes et al 3 report the 10-year results of this study. CALGB9343wasstatisticallydesignedasasuperioritytrialtotest whether radiation would reduce the probability of breast recurrence. With respect to this end point, the study was positive in favor of radiation. Specifically, the 10-year breast recurrence rates were 10% without radiation versus 2% with radiation (P .001). The updated report also demonstrated that the hazard of developing breast recurrence without radiation seemed similar between years 5 and 10 compared with thefirst 5 years of follow-up and that the risk would likely continue to increase after 10 years. This is consistent with previously published data indicating that ER-positive disease requires decades of follow-up to determine the true recurrence risk and the true magnitude of treatment benefits. 4
Safety of Prior Endoscopic Mucosal Resection in Patients Receiving Radiofrequency Ablation of Barrett's Esophagus
Authors: Ngozi I. Okoro, Yutaka Tomizawa, Kelly T. Dunagan, Lori S. Lutzke, Kenneth K. Wang, Ganapathy A. Prasad
Journal: Clinical Gastroenterology and Hepatology (2011)
Impact of Percutaneous Device Implantation for Closure of Patent Foramen Ovale on Valve Insufficiencies
Authors: Jochen Wöhrle, Matthias Kochs, Jochen Spiess, Thorsten Nusser, Vinzenz Hombach, Nico Merkle
Journal: Circulation (2009)

Background— In patients with percutaneous device implantation for closure of patent foramen ovale (PFO), a 10% incidence of new or worsened aortic regurgitation within 12 months has been reported with echocardiography. Cardiac magnetic resonance imaging is a powerful noninvasive tool to quantify volume and fraction of valve insufficiencies. We studied the acute and long-term impact of percutaneous device implantation for PFO closure on valve insufficiencies in cardiac magnetic resonance imaging. Methods and Results— Sequential cardiac magnetic resonance imaging studies were performed in 102 patients with cryptogenic ischemic events. Cardiac magnetic resonance imaging was performed before PFO closure, the day after device implantation, and at 12 months of follow-up. There was no difference in volumetric and hemodynamic parameters before PFO closure compared with 12 months of follow-up. With a cutoff for relevant regurgitation fraction of 5%, there were no statistically significant differences in regurgitation fraction of the semilunar and atrioventricular valves. The median fraction of aortic valve insufficiency was 3.9% (interquartile range [IQR] 2.0% to 5.1%) before PFO closure, 5.4% (IQR 4.1% to 5.9%) after device implantation, and 4.3% (IQR 3.3% to 6.0%) at 12 months of follow-up. The size and type of the occluder had no impact on aortic valve insufficiency. Median regurgitation fraction for the pulmonary valve was 3.6% (IQR 2.4% to 6.7%) before intervention, 7.3% (IQR 5.1% to 8.2%) after occluder implantation and 5.8% (IQR 4.8% to 7.4%) at 12 months of follow-up. Values for the mitral valve were 3.1% (IQR 1.4% to 6.0%), 5.5% (IQR 3.5% to 7.3%), and 3.8% (IQR 1.5% to 7.9%) and for the tricuspid valve were 5.4% (IQR 0.1% to 8.8%), 5.8% (IQR 1.4% to 9.2%), and 6.0% (IQR 1.1% to 8.4%), respectively. Conclusions— Percutaneous PFO closure with device implantation has no impact on valve insufficiencies as determined by cardiac magnetic resonance imaging.
Evaluation of the Xpert MTB/RIF Assay for the Diagnosis of Pulmonary Tuberculosis in a High HIV Prevalence Setting
Authors: Grant Theron, Jonny Peter, Richard van Zyl-Smit, Hridesh Mishra, Elizabeth Streicher, Samuel Murray, Rodney Dawson, Andrew Whitelaw, Michael Hoelscher, Surendra Sharma, Madhukar Pai, Robin Warren, Keertan Dheda
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Xpert MTB/RIF is a novel automated molecular diagnostic recently endorsed by the World Health Organization. However, performance-related data from high HIV prevalence settings are limited.The impact of sample-related factors on performance and the significance of Xpert MTB/RIF-positive culture-negative discordance remain unclear.Xpert MTB/RIF was evaluated using single archived spot-sputum samples from 496 South African patients with suspected TB. Mycobacterium tuberculosis culture positivity and phenotypic resistance to rifampicin served as reference standards.Overall, Xpert MTB/RIF detected 95% (95% confidence interval [CI], 88-98%; 89 of 94) of smear-positive culture-positive cases and the specificity was 94% (91-96%; 320 of 339). The sensitivity in smear-negative cases was 55% (35-73%; 12 of 22) when the analysis was restricted to 1 ml of unprocessed sputum and culture time-to-positivity of less than or equal to 28 days. Compared with smear microscopy (n=94), Xpert MTB/RIF detected an additional 17 cases (n=111) representing an 18% (11-27%; 111 vs. 94) relative increase in the rapid TB case detection rate. Moreover, compared with smear microscopy, the inclusion of Xpert MTB/RIF-positive culture-negative TB cases (ruled-in by an alternative diagnostic method) resulted in the detection of a further 16 cases (n=127), thus significantly increasing the rapid TB case detection rate to 35% (95% CI, 26-45%; 94 to 111 vs. 94 to 127; P<0.01), the overall specificity to 99.1% (97-100%; 320 of 323; P<0.001), and sensitivity in smear-negative TB to 60% (P=0.12). Performance strongly correlated with smear status and culture time-to-positivity. In patients infected with HIV compared with patients uninfected with HIV Xpert MTB/RIF showed a trend to reduced sensitivity (P=0.09) and significantly reduced negative predictive value (P=0.01). The negative predictive value for rifampicin resistance was 99.4%.XpertMTB/RIF outperformed smear microscopy, established a diagnosis in a significant proportion of patients with smear-negative TB, detected many highly likely TB cases missed by culture, and accurately ruled out rifampicin-resistant TB. Sample-specific factors had limited impact on performance. Performance in patients infected with HIV, especially those with advanced immunosuppression, warrants further study.
Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide
Authors: S. Homma, A. Miyamoto, S. Sakamoto, K. Kishi, N. Motoi, K. Yoshimura
Journal: European Respiratory Journal (2005)

Despite the increasing industrial use of indium-tin oxide (ITO) to manufacture flat-panel displays, such as liquid-crystal displays or plasma display panels for televisions, little is known about the potential health hazard induced by occupational exposure to indium compounds. The current study describes a case of fibrotic lung disease that developed after a 4-yr exposure to ITO. The pathology of the lung demonstrated pulmonary fibrosis with the presence of cholesterol granulomas. In conclusion, more attention needs to be paid to the possible toxic effects of indium compounds, and maximum healthcare measures should be taken to protect industry workers from these toxicities.
Reentrant Wave Fronts in Wiggers’ Stage II Ventricular Fibrillation
Authors: John J. Lee, Kamyar Kamjoo, Dustan Hough, Chun Hwang, Wei Fan, Michael C. Fishbein, Claudio Bonometti, Takanori Ikeda, Hrayr S. Karagueuzian, Peng-Sheng Chen
Journal: Circulation Research (1996)

Abstract The mechanisms of Wiggers’ stage II ventricular fibrillation (VF) are poorly understood. Using computerized mapping techniques, we studied the patterns of activation during Wiggers’ stage II VF in 13 open-chest dogs. In 7 of the 13 dogs, the right ventricular Purkinje fibers and adjacent subendocardial myocytes were ablated with Lugol solution. VF was induced electrically, and 3 to 5 seconds of data were obtained beginning ≈2.5 seconds after the onset of VF. Dynamic displays of the activation patterns and isochronal maps revealed the presence of reentrant wave fronts in 17 of 33 runs of VF in ablated ventricles and in 12 of 45 runs of VF in intact ventricles. The incidence of reentry was not different between the subendocardium-ablated group versus the nonablated group (1.7±1.6 versus 1.2±1.6 rotations per episode of VF, P =.19). There were no differences in the core size (25±19 versus 29±18 mm 2 ), life span (3.4±1.1 versus 3.2±1.2 rotations), or cycle length (111±12 versus 107±8 ms) in ablated ventricles versus intact ventricles, respectively. The core was unstable as it meandered within the mapped area displacing the entire reentrant wave front. In all episodes, the reentrant wave fronts were spontaneously initiated by an interaction between two propagating wave fronts roughly perpendicular to each other. The second wave front met the tail of the first wave front 69±11 ms (range, 40 to 90 ms) after its latest activation, indicating that the interaction occurred during a vulnerable period. The reentrant wave fronts terminated spontaneously (n=7), as the result of interference by an invading wave front (n=19), or meandered off the mapped region (n=3). We conclude the following: (1) Reentrant activities with short life spans and meandering cores are present during Wiggers’ stage II VF in dogs. (2) New reentrant wave fronts are generated when one wave front interacts with another wave front during its vulnerable period. (3) The reentrant wave fronts terminate spontaneously or as the result of interference. (4) Chemical subendocardial ablation does not affect the incidence, life span, cycle length, or core size of the reentrant wave fronts.
Macrophages phagocytose thymic lymphocytes with productively rearranged T cell receptor alpha and beta genes.
Authors: K Inaba, M Inaba, T Kinashi, K Tashiro, M Witmer-Pack, M Crowley, G Kaplan, J Valinsky, N Romani, S Ikehara
Journal: The Journal of Experimental Medicine (1988)

The thymus gland is important for the formation of competent T lymphocytes. However, there is long-standing evidence that greater than 95% of newly formed thymocytes do not emigrate to peripheral lymphoid tissues but instead die locally. We have identified a rapid and selective pathway for thymocyte turnover in vitro. The mechanism entails binding, uptake, and digestion by macrophages. The susceptible cells are a subpopulation of double-positive thymocytes. These thymocytes can be enriched by virtue of their high buoyant density in Percoll and prove to have low levels of surface CD3 and little or no surface TCR. However TCR-alpha and -beta genes have undergone rearrangement, and full length alpha and beta transcripts are abundant. Therefore many double-positive cells rearrange and express TCR genes but do not have normal levels of TCR on the cell surface. We propose that thymocytes that undergo high turnover in situ are unable to form receptors that can be selected by MHC molecules in the thymus, and that these cells are recognized and cleared by the macrophage.
Lymphokine-Activated Killer T-Cell-Originated Protein Kinase Phosphorylation of Histone H2AX Prevents Arsenite-Induced Apoptosis in RPMI7951 Melanoma Cells
Authors: Tatyana A. Zykova, Feng Zhu, Chengrong Lu, LeeAnn Higgins, Yasuaki Tatsumi, Yasuhito Abe, Ann M. Bode, Zigang Dong
Journal: Clinical Cancer Research (2006)

Arsenic is a valuable therapeutic tool in cancer treatment. Lymphokine-activated killer T-cell-originated protein kinase (TOPK) is highly expressed in cancer cells, but its specific function is still unknown. We investigated the role of TOPK in arsenic-induced apoptosis in RPMI7951 human melanoma cells.Expression of TOPK was evaluated in different melanoma cell lines, and liquid chromatography-tandem mass spectrometry analysis was used to identify proteins binding with TOPK. Immunofluorescence, Western blot, and flow cytometry were used to assess the effect of arsenic on TOPK, histone H2AX, and apoptosis in RPMI7951 cells.Melanoma cell lines expressing high levels of TOPK were more resistant to arsenite (As(3+))-induced apoptosis. As(3+) treatment induced phosphorylation of TOPK and histone H2AX in RPMI7951 human melanoma cells. Liquid chromatography-tandem mass spectrometry results indicated that TOPK could bind with histone H2AX, and in vitro and in vivo assays confirmed that TOPK binds with and phosphorylates histone H2AX. As(3+) treatment caused phosphorylation of TOPK, which colocalized with phosphorylated histone H2AX in the nucleus. TOPK small interfering RNA cells exhibited a decreased phosphorylation of histone H2AX with As(3+) treatment. As(3+)-induced apoptosis was decreased in H2AX(-/-) cells but increased in TOPK small interfering RNA cells.TOPK binds with histone H2AX and inhibits As(3+)-induced apoptosis through phosphorylation of histone H2AX. Melanoma cell lines with high levels of TOPK are more resistant to As(3+)-induced apoptosis. Therefore, inhibition of TOPK activity combined with As(3+) treatment may be helpful in the treatment of melanomas.
Growth Inhibition With Reversible Cell Cycle Arrest of Carcinoma Cells by Flavone L86-8275
Authors: G. Kaur, M. Stetler-Stevenson, S. Sebers, P. Worland, H. Sedlacek, C. Myers, J. Czech, R. Naik, E. Sausville
Journal: JNCI Journal of the National Cancer Institute (1992)

Previous studies have shown that polyhydroxylated flavonoids such as quercetin and genistein can inhibit tumor cell growth in vitro, and preliminary in vivo studies of the flavone L86-8275 have shown growth inhibition of LX529 and A549 lung carcinomas. L86-8275 [(-)cis-5,7-dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1-methyl)- piperidinyl]-4H-1-benzopyran-4-one] is a flavone of novel structure.The purpose of this study was to determine in vitro whether L86-8275 is a more potent inhibitor of growth in breast carcinoma and lung carcinoma cells than quercetin or genistein.We studied the effects of L86-8275 on cell growth in seven breast carcinoma cell lines and five lung carcinoma cell lines. MDA468 breast carcinoma was then selected for further study. Cell proliferation was measured by a colorimetric dye reduction assay; synthesis of DNA, RNA, and protein by incorporation of the radioactive metabolic precursors thymidine, uridine, or leucine, respectively; adenosine triphosphate (ATP) content by a luciferase-mediated bioluminescence reaction; and cell cycle progression by the use of cell-synchronizing drugs (aphidicolin and nocodazole) and flow cytometry.L86-8275 was not cytotoxic to stationary-phase cells but reversibly inhibited the growth of cells in exponential growth phase. At concentrations of 25-160 nM, L86-8275 inhibited growth of human breast and lung carcinoma cell lines by 50%. MDA468 breast carcinoma cells were 60-fold and 400-fold more sensitive to L86-8275 than to quercetin and genistein, respectively. By 24 hours after addition of L86-8275, DNA synthesis in MDA468 cells was inhibited by greater than 95%, protein synthesis by 80%, and RNA synthesis by 40%-60%, under conditions that preserved cellular ATP levels at approximately 80%-90% of control values. When MDA468 cells released from aphidicolin-induced cell cycle arrest were exposed to 200 nM L86-8275, they completed the S phase but arrested in G2. When cells released from nocodazole-induced cell cycle arrest were exposed to 200 nM L86-8275, they completed mitosis but arrested in G1.L86-8275 is a potent, yet reversible, growth-inhibitory flavone that can selectively block cell cycle progression in vitro at more than one point in the cell cycle.These findings suggest that L86-8275 is a candidate for further preclinical development, as well as a model for the synthesis of other flavonoids that might potently delay cell cycle progression to achieve inhibition of tumor growth. Future studies need to address optimal schedules for antiproliferative activity in vivo and inhibition of clonogenic activity.
Tau exon 10 alternative splicing and tauopathies
Authors: Fei Liu, Cheng-Xin Gong
Journal: Molecular Neurodegeneration (2008)

Abnormalities of microtubule-associated protein tau play a central role in neurofibrillary degeneration in several neurodegenerative disorders that collectively called tauopathies. Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively). Approximately equal levels of 3R-tau and 4R-tau are expressed in normal adult human brain, but the 3R-tau/4R-tau ratio is altered in the brains in several tauopathies. Discovery of silence mutations and intronic mutations of tau gene in some individuals with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), which only disrupt tau exon 10 splicing but do not alter tau's primary sequence, demonstrates that dysregulation of tau exon 10 alternative splicing and consequently of 3R-tau/4R-tau balance is sufficient to cause neurodegeneration and dementia. Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau. Finally, dysregulation of exon 10 splicing of tau in several tauopathies is discussed. Understanding the molecular mechanisms by which tau exon 10 splicing is regulated and how it is disrupted in tauopathies will provide new insight into the mechanisms of these tauopathies and help identify new therapeutic targets to treat these disorders.
Randomized Controlled Trial of Resistance or Aerobic Exercise in Men Receiving Radiation Therapy for Prostate Cancer
Authors: Roanne J. Segal, Robert D. Reid, Kerry S. Courneya, Ronald J. Sigal, Glen P. Kenny, Denis G. Prud'Homme, Shawn C. Malone, George A. Wells, Chris G. Scott, Monika E. Slovinec D'Angelo
Journal: Journal of Clinical Oncology (2008)

Radiotherapy for prostate cancer (PCa) may cause unfavorable changes in fatigue, quality of life (QOL), and physical fitness. We report results from the Prostate Cancer Radiotherapy and Exercise Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue, QOL, physical fitness, body composition, prostate-specific antigen, testosterone, hemoglobin, and lipid levels in men with PCa receiving radiotherapy.Between 2003 and 2006, we conducted a randomized controlled trial in Ottawa, Canada, where 121 PCa patients initiating radiotherapy with or without androgen deprivation therapy were randomly assigned to usual care (n = 41), resistance (n = 40), or aerobic exercise (n = 40) for 24 weeks. Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale.The follow-up assessment rate for our primary end point of fatigue was 92.6%. Median adherence to prescribed exercise was 85.5%. Mixed-model repeated measures analyses indicated both resistance (P =.010) and aerobic exercise (P = .004) mitigated fatigue over the short term. Resistance exercise also produced longer-term improvements (P = .002). Compared with usual care, resistance training improved QOL (P = .015), aerobic fitness (P = .041), upper- (P < .001) and lower-body (P < .001) strength, and triglycerides (P = .036), while preventing an increase in body fat (P = .049). Aerobic training also improved fitness (P = .052). One serious adverse event occurred in the group that performed aerobic exercise.In the short term, both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy. Resistance exercise generated longer-term improvements and additional benefits for QOL, strength, triglycerides, and body fat.
Identification of cis-regulatory sequence variations in individual genome sequences
Authors: Rebecca Worsley-Hunt, Virginie Bernard, Wyeth W Wasserman
Journal: Genome Medicine (2011)

Functional contributions of cis-regulatory sequence variations to human genetic disease are numerous. For instance, disrupting variations in a HNF4A transcription factor binding site upstream of the Factor IX gene contributes causally to hemophilia B Leyden. Although clinical genome sequence analysis currently focuses on the identification of protein-altering variation, the impact of cis-regulatory mutations can be similarly strong. New technologies are now enabling genome sequencing beyond exomes, revealing variation across the non-coding 98% of the genome responsible for developmental and physiological patterns of gene activity. The capacity to identify causal regulatory mutations is improving, but predicting functional changes in regulatory DNA sequences remains a great challenge. Here we explore the existing methods and software for prediction of functional variation situated in the cis-regulatory sequences governing gene transcription and RNA processing.