tbuckley/cabot-search huggingface dataset:
Oxidative Stress Is Inherent in Prostate Cancer Cells and Is Required for Aggressive Phenotype
Authors: Binod Kumar, Sweaty Koul, Lakshmipathi Khandrika, Randall B. Meacham, Hari K. Koul
Journal: Cancer Research (2008)

Abstract Reactive oxygen species (ROS) and the coupled oxidative stress have been associated with tumor formation. Several studies suggested that ROS can act as secondary messengers and control various signaling cascades. In the present studies, we characterized the oxidative stress status in three different prostate cancer cells (PC3, DU145, and LNCaP) exhibiting various degree of aggressiveness and normal prostate cells in culture (WPMY1, RWPE1, and primary cultures of normal epithelial cells). We observed increased ROS generation in cancer cells compared with normal cells, and that extramitochondrial source of ROS generator, NAD(P)H oxidase (Nox) systems, are associated with the ROS generation and are critical for the malignant phenotype of prostate cancer cells. Moreover, diphenyliodonium, a specific Nox inhibitor, blocked proliferation, modulated the activity of growth signaling cascades extracellular signal-regulated kinase (ERK)1/ERK2 and p38 mitogen-activated protein kinase as well as AKT protein kinaseB, and caused cyclin B–dependent G2-M cell cycle arrest. We also observed higher degrees of ROS generation in the PC3 cells than DU145 and LNCaP, and that ROS generation is critical for migratory/invasiveness phenotypes. Furthermore, blocking of the ROS production rather than ROS neutralization resulted in decreased matrix metalloproteinase 9 activity as well as loss of mitochondrial potential, plausible reasons for decreased cell invasion and increased cell death. Taken together, these studies show, for the first time, the essential role of ROS production by extramitochondrial source in prostate cancer and suggest that therapies aimed at reducing ROS production might offer effective means of combating prostate cancer in particular, and perhaps other malignancies in general. [Cancer Res 2008;68(6):1777–85]
Editorial
Authors: EUGENE A. STEAD
Journal: Circulation (1965)

Pressures and PulsesT HE rhythmical beating of the heart and the resultant changes in flow and pres- sure in the arterial system have always fas- cinated both the lay public and physicians.Most physicians feel the pulse and record the blood pressure.Over the years these actions become so automatic that one frequently for- gets the anatomic and physiologic factors that modify the pulse and blood pressure.The left ventricle rhythmically forces blood into the aorta.The arterial system gains in energy with each systolic contraction.The majority of this energy is used in accelerating blood, in distending the walls of the aorta, in increasing the pressure in the arterial system, and in overcoming viscous resistance to flow.The total energy added to the system cannot be calculated by the measurement of any single factor such as lateral pressure.The energy added to the system by ven- tricular contraction, which is not lost as heat, may reappear as lateral pressure.The blood can be decelerated, the aorta may decrease in volume because of elastic recoil, and the energy of pressure fed into areas of low flow may be returned to the central system to be converted into kinetic energy in areas of rapid flow.In a closed rigid system of tubes, any' in- crease in volume of a noncompressible liquid will cause an immediate increase in pres-
Pregabalin in Generalized Anxiety Disorder: A Placebo-Controlled Trial
Authors: Atul C. Pande, Jerri G. Crockatt, Douglas E. Feltner, Carol A. Janney, Ward T. Smith, Richard Weisler, Peter D. Londborg, Robert J. Bielski, Dan L. Zimbroff, Jonathan R.T. Davidson, Maria Liu-Dumaw
Journal: American Journal of Psychiatry (2003)

Current drug therapies for generalized anxiety disorder have limitations. In a controlled trial, the novel agent pregabalin was studied for the treatment of patients with generalized anxiety disorder.In this double-blind study, patients with DSM-IV generalized anxiety disorder were randomly assigned to receive pregabalin (150 mg/day or 600 mg/day), lorazepam (6 mg/day), or placebo. A 1-week placebo lead-in was followed by 4 weeks of treatment and then a 1-week dose taper. The primary efficacy measure was the Hamilton Anxiety Rating Scale score at endpoint.A total of 276 patients were randomly assigned to a treatment group and received at least one dose of their assigned medication. Fewer patients given lorazepam (59%, N=40 of 68) completed the trial than did those given placebo (73%, N=50 of 69), 600 mg/day of pregabalin (71%, N=50 of 70), or 150 mg/day or pregabalin (90%, N=62 of 69). The mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the patients given 150 mg/day of pregabalin (-9.2), 600 mg/day of pregabalin (-10.3), and lorazepam (-12.0) were significantly greater than the decrease in those given placebo (-6.8). As early as the week 1 observation, pregabalin significantly reduced the total Hamilton anxiety scale score compared with placebo. The most frequent adverse events reported for pregabalin and lorazepam were somnolence and dizziness. There were no serious adverse events reported by patients given pregabalin, and no withdrawal syndrome was associated with pregabalin treatment.These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines.
The mouse DXZ4 homolog retains Ctcf binding and proximity to Pls3 despite substantial organizational differences compared to the primate macrosatellite
Authors: Andrea H Horakova, J Mauro Calabrese, Christine R McLaughlin, Deanna C Tremblay, Terry Magnuson, Brian P Chadwick
Journal: Genome biology (2012)

Abstract Background The X-linked macrosatellite DXZ4 is a large homogenous tandem repeat that in females adopts an alternative chromatin organization on the primate X chromosome in response to X-chromosome inactivation. It is packaged into heterochromatin on the active X chromosome but into euchromatin and bound by the epigenetic organizer protein CTCF on the inactive X chromosome. Because its DNA sequence diverges rapidly beyond the New World monkeys, the existence of DXZ4 outside the primate lineage is unknown. Results Here we extend our comparative genome analysis and report the identification and characterization of the mouse homolog of the macrosatellite. Furthermore, we provide evidence of DXZ4 in a conserved location downstream of the PLS3 gene in a diverse group of mammals, and reveal that DNA sequence conservation is restricted to the CTCF binding motif, supporting a central role for this protein at this locus. However, many features that characterize primate DXZ4 differ in mouse, including the overall size of the array, the mode of transcription, the chromatin organization and conservation between adjacent repeat units of DNA sequence and length. Ctcf binds Dxz4 but is not exclusive to the inactive X chromosome, as evidenced by association in some males and equal binding to both X chromosomes in trophoblast stem cells. Conclusions Characterization of Dxz4 reveals substantial differences in the organization of DNA sequence, chromatin packaging, and the mode of transcription, so the potential roles performed by this sequence in mouse have probably diverged from those on the primate X chromosome.
An integrated transcriptome and expressed variant analysis of sepsis survival and death
Authors: Ephraim L Tsalik, Raymond J Langley, Darrell L Dinwiddie, Neil A Miller, Byunggil Yoo, Jennifer C van Velkinburgh, Laurie D Smith, Isabella Thiffault, Anja K Jaehne, Ashlee M Valente, Ricardo Henao, Xin Yuan, Seth W Glickman, Brandon J Rice, Micah T McClain, Lawrence Carin, G Ralph Corey, Geoffrey S Ginsburg, Charles B Cairns, Ronny M Otero, Vance G Fowler, Emanuel P Rivers, Christopher W Woods, Stephen F Kingsmore
Journal: Genome Medicine (2014)

Abstract Background Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality. Methods The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes. Results The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1 , whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology. Conclusions The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies. Trial registration ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.
Acute Effect of Methadone Maintenance Dose on Brain fMRI Response to Heroin-Related Cues
Authors: Daniel D. Langleben, Kosha Ruparel, Igor Elman, Samantha Busch-Winokur, Ramapriyan Pratiwadi, James Loughead, Charles P. O’Brien, Anna R. Childress
Journal: American Journal of Psychiatry (2007)

Objective: Environmental drug-related cues have been implicated as a cause of illicit heroin use during methadone maintenance treatment of heroin dependence. The authors sought to identify the functional neuroanatomy of the brain response to visual heroin-related stimuli in methadone maintenance patients. Method: Event-related functional magnetic resonance imaging was used to compare brain responses to heroin-related stimuli and matched neutral stimuli in 25 patients in methadone maintenance treatment. Patients were studied before and after administration of their regular daily methadone dose. Results: The heightened responses to heroin-related stimuli in the insula, amygdala, and hippocampal complex, but not the orbitofrontal and ventral anterior cingulate cortices, were acutely reduced after administration of the daily methadone dose. Conclusions: The medial prefrontal cortex and the extended limbic system in methadone maintenance patients with a history of heroin dependence remains responsive to salient drug cues, which suggests a continued vulnerability to relapse. Vulnerability may be highest at the end of the 24-hour interdose interval.
Temporal Trends in Early Clinical Manifestations of Perinatal HIV Infection in a Population-Based Cohort
Authors: David R. Berk
Journal: JAMA (2005)

ContextThe effect of early antiretroviral therapy (ART) on the early progression of perinatal human immunodeficiency virus (HIV) infection is not well defined.ObjectiveTo examine early disease progression and survival in a population-based cohort with perinatal HIV infection in relation to year of birth and use of ART.Design, Setting, and PatientsRetrospective study of temporal trends in early progression of perinatal HIV infection among 205 HIV-infected children in Northern California born between January 1, 1988, and December 31, 2001, and followed up through age 3 years.Main Outcome MeasuresPrevalence of and age at progression to a first US Centers for Disease Control and Prevention category C diagnosis relative to year of birth, type of ART, and age at initiation of therapy.ResultsOf 205 children, 134 (65%) received ART and/or Pneumocystis jiroveci pneumonia prophylaxis. By age 3 years, 81 (40%) progressed to a category C diagnosis, 41 (51%) of whom died. Untreated children were significantly more likely to progress to a category C diagnosis (62% [44/71] untreated vs 28% [37/134] treated children, P<.001); none of 23 infants who received triple ART progressed to category C. However, even without triple ART, very early mono/dual ART (by age 2 months vs 3-4 months) was associated with delayed and decreased progression to category C (P = .02). Of 33 children born between January 1, 1996, and December 31, 2001, only 7 (21%) progressed to category C (P = .02 compared with 1988-1995), 6 of 7 of whom received no therapy. More recent year of birth and more advanced therapy were associated with improved survival.ConclusionsThis population-based cohort demonstrated decreased early HIV progression and improved survival at age 3 years, associated with more advanced therapy. Although limited by small sample size, the findings suggest that very early treatment, even without triple ART, was associated with improved outcome.
RT-07 * APPLICATION OF A GROWTH-RATE BASED RESPONSE METRIC TO RECURRENT MALIGNANT GLIOMAS TREATED WITH LARGE-VOLUME RE-IRRADIATION USING PROTON BEAM THERAPY
Authors: B. Desai, R. Rockne, C. Bridge, D. Corwin, J. Crisman, I. Helenowski, E. Kokkinos, C. Peters, A. Rosenberg, D. Sharfman, V. Gondi, K. Swanson
Journal: Neuro-Oncology (2014)

BACKGROUND: The Days Gained (DG) response metric, which incorporates knowledge of the tumor growth rate, has been shown to correlate with progression-free (PFS) and overall survival (OS) following concurrent chemoradiotherapy for newly diagnosed glioblastoma (Neal et al., 2013 PLOS One; Neal et al., 2013 Cancer Research). We describe the first use of this metric to analyze radiographic response of recurrent malignant gliomas to large-volume re-irradiation using proton beam therapy (PBT). METHODS: The equation described in Neal, et al., 2013 was utilized to derive the DG score for 8 patients with histologically confirmed, contrast-enhancing recurrent gliomas. For each patient, the DG response metric was calculated from the enhancing T1 + Gad sequences of 2 MRIs immediately prior to PBT and the first MRI following completion of PBT. OS time from PT start was estimated with Kaplan-Meier analysis; comparisons used log-rank statistic. RESULTS: Median age was 43, median KPS score was 90, and median number of salvage treatments was 2. The mean DG score was 78.8 (range: -32.3-276.8). Concomitant use of temozolomide and bevacizumab during PBT was associated with a higher mean DG score (191.2 vs. 11.4; p = 0.03). In addition, association between higher DG score and superior OS trended to statistical significance (HR = 0.986, p = 0.08). CONCLUSIONS: First analysis of radiographic response of recurrent malignant gliomas to re-irradiation using PBT supports a possible association between DG and OS and the prolongation of DG with the concomitant use of temozolomide and bevacizumab during re-irradiation. Further analysis with larger sample size remains ongoing.
The effect of glucosamine supplementation on people experiencing regular knee pain * Commentary
Authors: R Braham, B Dawson, C Goodman
Journal: British Journal of Sports Medicine (2003)

The purpose of this study was to examine the effects of oral glucosamine supplementation on the functional ability and degree of pain felt by individuals who had regular knee pain, most likely due to previous articular cartilage damage, and possibly osteoarthritis.Subjects were randomly supplemented with either glucosamine (G) (n=24) or placebo (P) (lactose) (n=22) for 12 weeks at a dose of 2,000 mg per day. Over this period, four testing sessions were conducted, with changes in knee pain and function assessed by clinical and functional tests, (joint line palpation, a 3 metre "duck walk" and a repeated, walking stair climb), two questionnaires (the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Knee Pain Scale (KPS)) and participant subjective evaluations.The clinical and functional test scores improved with time (main effects: p<0.05, p<0.01) but there were no significant differences between the two groups. The questionnaire results also recorded a significant main effect for time (p<0.05), but the glucosamine group was found to have significantly better KOOS quality of life scores at week eight and 12 (p<0.05), and lower KPS scores (p<0.05) at week eight than the placebo group. On self report evaluations of changes across the 12 week supplementation period, 88% (n=21) of the glucosamine group reported some degree of improvement in their knee pain versus only 17% (n=3) in the placebo group.These results suggest that glucosamine supplementation can provide some degree of pain relief and improved function in persons who experience regular knee pain, which may be caused by prior cartilage injury and/or osteoarthritis. The trends in the results also suggest that, at a dosage of 2,000 mg per day, the majority of improvements are present after eight weeks.
Ulcerative colitis and carcinoma of the proximal bile ducts
Authors: A. P. Ross, J. W. Braasch
Journal: Gut (1973)

In a review of 103 patients with carcinoma of the proximal bile ducts, eight patients were noted to have had ulcerative colitis also. This finding is strongly suggestive of a specific association between the two diseases. In three of the patients, carcinoma developed several years after proctocolectomy. Seven of the eight patients were significantly younger than the median age of the group as a whole, but no other apparent difference was noted between those with ulcerative colitis and the remainder of the group.
Transendothelial Migration of Megakaryocytes in Response to Stromal Cell-derived Factor 1 (SDF-1) Enhances Platelet Formation
Authors: Tsuneyoshi Hamada, Robert Möhle, Joseph Hesselgesser, James Hoxie, Ralph L. Nachman, Malcolm A.S. Moore, Shahin Rafii
Journal: The Journal of Experimental Medicine (1998)

Although thrombopoietin has been shown to promote megakaryocyte (MK) proliferation and maturation, the exact mechanism and site of platelet formation are not well defined. Studies have shown that MKs may transmigrate through bone marrow endothelial cells (BMEC), and release platelets within the sinusoidal space or lung capillaries. In search for chemotactic factor(s) that may mediate transmigration of MKs, we have discovered that mature polyploid MKs express the G protein–coupled chemokine receptor CXCR4 (Fusin, LESTR). Therefore, we explored the possibility that stromal cell–derived factor 1 (SDF-1), the ligand for CXCR4, may also induce transendothelial migration of mature MKs. SDF-1, but not other CXC or CC chemokines, was able to mediate MK migration (ED50 = 125 pmol/liter). The MK chemotaxis induced by SDF-1 was inhibited by the CXCR4-specific mAb (12G5) and by pertussis toxin, demonstrating that signaling via the G protein–coupled receptor CXCR4 was necessary for migration. SDF-1 also induced MKs to migrate through confluent monolayers of BMEC by increasing the affinity of MKs for BMEC. Activation of BMEC with interleukin 1β resulted in a threefold increase in the migration of MKs in response to SDF-1. Neutralizing mAb to the endothelial-specific adhesion molecule E-selectin blocked the migration of MKs by 50%, suggesting that cellular interaction of MKs with BMEC is critical for the migration of MKs. Light microscopy and ploidy determination of transmigrated MKs demonstrated predominance of polyploid MKs. Virtually all platelets generated in the lower chamber also expressed CXCR4. Platelets formed in the lower chamber were functional and expressed P-selectin (CD62P) in response to thrombin stimulation. Electron microscopy of the cells that transmigrated through the BMEC monolayers in response to SDF-1 demonstrated the presence of intact polyploid MKs as well as MKs in the process of platelet formation. These results suggest that SDF-1 is a potent chemotactic factor for mature MKs. Expression of CXCR4 may be the critical cellular signal for transmigration of MKs and platelet formation.
Relapse-Free and Overall Survival in Patients With Pathologic Stage II Nonseminomatous Germ Cell Cancer Treated With Etoposide and Cisplatin Adjuvant Chemotherapy
Authors: G. Varuni Kondagunta, Joel Sheinfeld, Madhu Mazumdar, Tania V. Mariani, Dean Bajorin, Jennifer Bacik, George J. Bosl, Robert J. Motzer
Journal: Journal of Clinical Oncology (2004)

To assess the long-term relapse-free survival and overall survival of patients with stage II nonseminomatous germ cell tumor (NSGCT) who received two cycles of adjuvant etoposide and cisplatin (EP) after primary retroperitoneal lymph node dissection.Eighty-seven patients with completely resected pathologic stage II NSGCT were treated with adjuvant EP chemotherapy. Adjuvant EP consisted of two cycles of etoposide (100 mg/m(2)) plus cisplatin (20 mg/m(2)) per day, administered days 1 to 5 at a 21-day interval.Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient received an additional two cycles of EP after a transient marker increase after his first cycle. Eighty-seven patients are alive, and 86 patients (99%) remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years).Two cycles of adjuvant EP is highly effective in preventing relapse in patients with pathologic stage II pN1 and pN2 NSGCT. An alternative treatment strategy is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy.
Pulmonary manifestations of hypogammaglobulinaemia.
Authors: R J Dukes, E C Rosenow, P E Hermans
Journal: Thorax (1978)

Fifty-five patients with late-onset idiopathic immunoglobulin deficiency were studied and upper or lower respiratory tract infections were encountered in about 90%. Cylindrical bronchiectasis was shown in all of the 21 patients in whom bronchograms were done. A thymoma was found in four patients. Three patients had diffuse interstitial pulmonary disease--two with proved and one with presumed lymphocytic interstitial pneumonitis. Five patients had no evidence of pulmonary disease, including two patients with long-standing late-onset immunoglobulin deficiency who had essentially no serum immunoglobulins. This small subgroup of patients with immunoglobulin dificiency without severe pulmonary infections cannot be explained in the context of current understanding of immunoglobulin deficiency. Thirty-two patients were followed up for long enough for the response to treatment to be assessed.