tbuckley/cabot-search huggingface dataset:
Region-specific radiotherapy and neuropsychological outcomes in adult survivors of childhood CNS malignancies
Authors: G. T. Armstrong, N. Jain, W. Liu, T. E. Merchant, M. Stovall, D. K. Srivastava, J. G. Gurney, R. J. Packer, L. L. Robison, K. R. Krull
Journal: Neuro-Oncology (2010)

Childhood cancer survivors exposed to CNS irradiation are at increased risk for neurocognitive deficits; however, limited data exist linking outcomes with region-specific exposure to CNS irradiation. We report associations between region-specific radiation dose and self-reported neurocognitive and health-related quality of life (HRQOL) outcomes in 818 adult survivors of childhood central nervous system (CNS) malignancies from the Childhood Cancer Survivor Study. Survivors were compared with a sibling group and national normative samples to calculate standardized scores. Cumulative radiation dose was calculated for 4 specific brain regions. Logistic regression was used to estimate the association between radiation dose to specific brain regions and outcome measures of functional impairment adjusted for clinical and demographic factors, including sex and age at diagnosis. High radiation dose levels to temporal regions were associated with a higher risk for memory impairment (radiation doses ≥30 to <50 Gy: OR, 1.95; 95% CI, 1.01–3.78; dose ≥50 Gy: OR, 2.34; 95% CI, 1.25–4.39) compared with those with no radiation exposure. No such association was seen with radiation exposure to other regions. Exposure to temporal regions was associated with more social and general health problems, whereas exposure to frontal regions was associated with general health problems and physical performance limitations. Adult survivors of childhood CNS malignancies report higher rates of neuropsychological and HRQOL outcomes, which vary as a function of dose to specific neuroanatomical regions. Survivors with a history of radiation exposure to temporal brain regions are at increased risk for impairment in memory and social functioning.
Clinical Overlap Among Medical Diagnosis-Related Groups
Authors: Lisa I. Iezzoni
Journal: JAMA (1986)

EVER since Congress enacted the hospital prospective payment system for Medicare in 1983, diagnostic semantics have come under increasing scrutiny. Under this reimbursement method, hospitals are paid a single, predetermined sum based on the patient's diagnosis-related group (DRG). The DRG system sorts the realm of "diagnoses" into 467 groups. However, the term<i>diagnosis</i>may be a misnomer. Some of the DRGs may be more appropriately called "symptom-related groups"—chest pain (DRG 143), for example. Others may be labeled "pathology-related groups" (atherosclerosis, DRGs 132 and 133), while still others may be best titled "severity-related groups" (heart failure and shock, DRG 127). This quibbling over the diagnostic lexicon may appear a trivial exercise unless one remembers that the DRG assignment dictates level of reimbursement. Each of the 467 DRGs has its own nationwide relative weight (RW) for reimbursement. Therefore, pecuniary incentives encourage close inspection of diagnostic phrasing to ensure patient allocation to the
Integrin α4β1–VCAM-1–mediated adhesion between endothelial and mural cells is required for blood vessel maturation
Authors: Barbara Garmy-Susini, Hui Jin, Yuhong Zhu, Rou-Jia Sung, Rosa Hwang, Judy Varner
Journal: Journal of Clinical Investigation (2005)

Neovascularization depends on vascular cell proliferation and on the stabilization of vessels by association of vascular smooth muscle-like pericytes with ECs. Here we show that integrin alpha4beta1 (VLA-4) and VCAM-1 promote close intercellular adhesion between ECs and pericytes and that this interaction is required for blood vessel formation. Integrin alpha4beta1 is expressed by proliferating but not quiescent ECs, while its ligand VCAM-1 is expressed by proliferating but not quiescent mural cells. Antagonists of this integrin-ligand pair block the adhesion of mural cells to proliferating endothelia in vitro and in vivo, thereby inducing apoptosis of ECs and pericytes and inhibiting neovascularization. These studies indicate that integrin alpha4beta1 and VCAM-1 facilitate a critical cell-cell adhesion event required for survival of endothelial and mural cells during vascularization.
The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas
Authors: Andrew R. Hallahan, Joel I. Pritchard, Stacey Hansen, Mark Benson, Jennifer Stoeck, Beryl A. Hatton, Thomas L. Russell, Richard G. Ellenbogen, Irwin D. Bernstein, Phillip A. Beachy, James M. Olson
Journal: Cancer Research (2004)

Abstract To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or γ secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a γ secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.
Hospital organisation, management, and structure for prevention of health-care-associated infection: a systematic review and expert consensus
Authors: Walter Zingg, Alison Holmes, Markus Dettenkofer, Tim Goetting, Federica Secci, Lauren Clack, Benedetta Allegranzi, Anna-Pelagia Magiorakos, Didier Pittet
Journal: The Lancet Infectious Diseases (2014)
A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Two Schedules of Vorinostat in Combination with 5-Fluorouracil and Leucovorin in Patients with Refractory Solid Tumors
Authors: Marwan G. Fakih, Gerald Fetterly, Merrill J. Egorin, Josephia R. Muindi, Igor Espinoza-Delgado, James A. Zwiebel, Alan Litwin, Julianne L. Holleran, Kangsheng Wang, Robert B. Diasio
Journal: Clinical Cancer Research (2010)

We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2).Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU.The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.
From co-expression to co-regulation: how many microarray experiments do we need?
Authors: Ka Yee Yeung, Mario Medvedovic, Roger E Bumgarner
Journal: Genome biology (2004)

Cluster analysis is often used to infer regulatory modules or biological function by associating unknown genes with other genes that have similar expression patterns and known regulatory elements or functions. However, clustering results may not have any biological relevance.We applied various clustering algorithms to microarray datasets with different sizes, and we evaluated the clustering results by determining the fraction of gene pairs from the same clusters that share at least one known common transcription factor. We used both yeast transcription factor databases (SCPD, YPD) and chromatin immunoprecipitation (ChIP) data to evaluate our clustering results. We showed that the ability to identify co-regulated genes from clustering results is strongly dependent on the number of microarray experiments used in cluster analysis and the accuracy of these associations plateaus at between 50 and 100 experiments on yeast data. Moreover, the model-based clustering algorithm MCLUST consistently outperforms more traditional methods in accurately assigning co-regulated genes to the same clusters on standardized data.Our results are consistent with respect to independent evaluation criteria that strengthen our confidence in our results. However, when one compares ChIP data to YPD, the false-negative rate is approximately 80% using the recommended p-value of 0.001. In addition, we showed that even with large numbers of experiments, the false-positive rate may exceed the true-positive rate. In particular, even when all experiments are included, the best results produce clusters with only a 28% true-positive rate using known gene transcription factor interactions.
The potential role of cobalt ions released from metal prosthesis on the inhibition of Hv1 proton channels and the decrease in Staphyloccocus epidermidis killing by human neutrophils
Authors: Samira Daou, Antoun El Chemaly, Panayiotis Christofilopoulos, Louis Bernard, Pierre Hoffmeyer, Nicolas Demaurex
Journal: Biomaterials (2010)
Fibroblast Growth Factor Receptor-1 Is Essential for In Vitro Cardiomyocyte Development
Authors: Patrizia Dell’Era, Roberto Ronca, Laura Coco, Stefania Nicoli, Marco Metra, Marco Presta
Journal: Circulation Research (2003)

Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a crucial role in mesoderm formation and patterning. Heartless mutant studies in Drosophila suggest that FGFR1, among the different FGFRs, may play a role in cardiogenesis. However, fgfr1 −/− mice die during gastrulation before heart formation. To establish the contribution of FGFR1 in cardiac development, we investigated the capacity of murine fgfr1 +/− and fgfr1 −/− embryonic stem (ES) cells to differentiate to cardiomyocytes in vitro. Clusters of pulsating cardiomyocytes were observed in &gt;90% of 3-dimensional embryoid bodies (EBs) originated from fgfr1 +/− ES cells at day 9 to 10 of differentiation. In contrast, 10% or less of fgfr1 −/− EBs showed beating foci at day 16. Accordingly, fgfr1 −/− EBs were characterized by impaired expression of early cardiac transcription factors Nkx2.5 and d-Hand and of late structural cardiac genes myosin heavy chain ( MHC )-α, MHC -β, and ventricular myosin light chain . Homozygous fgfr1 mutation resulted also in alterations of the expression of mesoderm-related early genes, including nodal , BMP2, BMP4 , T ( bra ), and sonic hedgehog . Nevertheless, fgfr1 +/− and fgfr1 −/− EBs similarly express cardiogenic precursor, endothelial, hematopoietic, and skeletal muscle markers, indicating that fgfr1 -null mutation exerts a selective effect on cardiomyocyte development in differentiating ES cells. Accordingly, inhibitors of FGFR signaling, including the FGFR1 tyrosine kinase inhibitor SU 5402, the MEK1/2 inhibitor U0126, and the protein kinase C inhibitor GF109 all prevented cardiomyocyte differentiation in fgfr1 +/− EBs without affecting the expression of the hematopoietic/endothelial marker flk-1 . In conclusion, the data point to a nonredundant role for FGFR1-mediated signaling in cardiomyocyte development.
miR-103/107 Promote Metastasis of Colorectal Cancer by Targeting the Metastasis Suppressors DAPK and KLF4
Authors: Hsin-Yi Chen, Yu-Min Lin, Hsiang-Ching Chung, Yaw-Dong Lang, Ching-Jung Lin, John Huang, Wei-Chi Wang, Feng-Mao Lin, Zhen Chen, Hsien-Da Huang, John Y.-J. Shyy, Jin-Tung Liang, Ruey-Hwa Chen
Journal: Cancer Research (2012)

Abstract Metastasis is the major cause of poor prognosis in colorectal cancer (CRC), and increasing evidence supports the contribution of miRNAs to cancer progression. Here, we found that high expression of miR-103 and miR-107 (miR-103/107) was associated with metastasis potential of CRC cell lines and poor prognosis in patients with CRC. We showed that miR-103/107 targeted the known metastasis suppressors death-associated protein kinase (DAPK) and Krüppel-like factor 4 (KLF4) in CRC cells, resulting in increased cell motility and cell–matrix adhesion and decreased cell–cell adhesion and epithelial marker expression. miR-103/107 expression was increased in the presence of hypoxia, thereby potentiating DAPK and KLF4 downregulation and hypoxia-induced motility and invasiveness. In mouse models of CRC, miR-103/107 overexpression potentiated local invasion and liver metastasis effects, which were suppressed by reexpression of DAPK or KLF4. miR-103/107–mediated downregulation of DAPK and KLF4 also enabled the colonization of CRC cells at a metastatic site. Clinically, the signature of a miR-103/107 high, DAPK low, and KLF4 low expression profile correlated with the extent of lymph node and distant metastasis in patients with CRC and served as a prognostic marker for metastasis recurrence and poor survival. Our findings therefore indicate that miR-103/107–mediated repression of DAPK and KLF4 promotes metastasis in CRC, and this regulatory circuit may contribute in part to hypoxia-stimulated tumor metastasis. Strategies that disrupt this regulation might be developed to block CRC metastasis. Cancer Res; 72(14); 3631–41. ©2012 AACR.
Urine Testing Schedules in Methadone Maintenance Treatment of Heroin Addiction
Authors: Avram Goldstein
Journal: JAMA (1970)

In the treatment of heroin addiction by methadone hydrochloride maintenance, it is customary to test urine specimens regularly, in order to monitor each patient's illicit use of drugs and to assess the general success of the program. Principles and graphs are presented here to aid the physician in choosing an economical testing frequency, and in interpreting the results quantitatively on a correct statistical basis. For most purposes, a random testing schedule at an average frequency of once in five days will suffice.
Maternal Blood, Plasma, and Breast Milk Lead: Lactational Transfer and Contribution to Infant Exposure
Authors: Adrienne S. Ettinger, Ananya Roy, Chitra J. Amarasiriwardena, Donald Smith, Nicola Lupoli, Adriana Mercado-García, Hector Lamadrid-Figueroa, Martha Maria Tellez-Rojo, Howard Hu, Mauricio Hernández-Avila
Journal: Environmental Health Perspectives (2013)

Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood.We explored the dose-response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant.We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose-response relationships between blood, plasma, and milk lead levels.Maternal lead levels (mean±SD) were as follows: blood: 7.7±4.0 μg/dL; plasma: 0.1±0.1 μg/L; milk: 0.8±0.7 μg/L. The average M/P lead ratio was 7.7 (range, 0.6-39.8) with 97% of the ratios being >1. The dose-response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function=6.5, p=0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 μg/L of plasma lead, respectively, below and above 0.1 μg/L plasma lead. Infant blood lead level (3.4±2.2 μg/dL) increased by 1.8 μg/dL per 1 μg/L milk lead (p<0.0001, R2=0.3).The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.
Initiation of Apoptosis by Granzyme B Requires Direct Cleavage of Bid, but Not Direct Granzyme B–Mediated Caspase Activation
Authors: Vivien R. Sutton, Joanne E. Davis, Michael Cancilla, Ricky W. Johnstone, Astrid A. Ruefli, Karin Sedelies, Kylie A. Browne, Joseph A. Trapani
Journal: The Journal of Experimental Medicine (2000)

The essential upstream steps in granzyme B–mediated apoptosis remain undefined. Herein, we show that granzyme B triggers the mitochondrial apoptotic pathway through direct cleavage of Bid; however, cleavage of procaspases was stalled when mitochondrial disruption was blocked by Bcl-2. The sensitivity of granzyme B–resistant Bcl-2–overexpressing FDC-P1 cells was restored by coexpression of wild-type Bid, or Bid with a mutation of its caspase-8 cleavage site, and both types of Bid were cleaved. However, Bid with a mutated granzyme B cleavage site remained intact and did not restore apoptosis. Bid with a mutation preventing its interaction with Bcl-2 was cleaved but also failed to restore apoptosis. Rapid Bid cleavage by granzyme B (&amp;lt;2 min) was not delayed by Bcl-2 overexpression. These results clearly placed Bid cleavage upstream of mitochondrial Bcl-2. In granzyme B–treated Jurkat cells, endogenous Bid cleavage and loss of mitochondrial membrane depolarization occurred despite caspase inactivation with z-Val-Ala-Asp-fluoromethylketone or Asp-Glu-Val-Asp-fluoromethylketone. Initial partial processing of procaspase-3 and -8 was observed irrespective of Bcl-2 overexpression; however, later processing was completely abolished by Bcl-2. Overall, our results indicate that mitochondrial perturbation by Bid is necessary to achieve a lethal threshold of caspase activity and cell death due to granzyme B.
Blocking eIF5A Modification in Cervical Cancer Cells Alters the Expression of Cancer-Related Genes and Suppresses Cell Proliferation
Authors: Elisabeth Mémin, Mainul Hoque, Mohit R. Jain, Debra S. Heller, Hong Li, Bernadette Cracchiolo, Hartmut M. Hanauske-Abel, Tsafi Pe'ery, Michael B. Mathews
Journal: Cancer Research (2013)

Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.
Influence of Nonfatal Hospitalization for Heart Failure on Subsequent Mortality in Patients With Chronic Heart Failure
Authors: Scott D. Solomon, Joanna Dobson, Stuart Pocock, Hicham Skali, John J.V. McMurray, Christopher B. Granger, Salim Yusuf, Karl Swedberg, James B. Young, Eric L. Michelson, Marc A. Pfeffer
Journal: Circulation (2007)

Background— Patients with chronic heart failure (HF) are at increased risk of both fatal and nonfatal major adverse cardiovascular events. We used data from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) trials to assess the influence of nonfatal hospitalizations for HF on subsequent mortality rates in a broad spectrum of HF patients. Methods and Results— In the present study, 7599 patients with New York Heart Association class II to IV HF and reduced or preserved left ventricular ejection fraction were randomized to placebo or candesartan. We assessed the risk of death after discharge from a first hospitalization for HF using time-updated Cox proportional-hazards models on 7572 patients for whom discharge data were available. Of 7572 patients, 1455 (19%) had at least 1 HF hospitalization, and 586 of 1819 deaths occurred after discharge from an HF hospitalization. The mortality rate was increased after HF hospitalizations, even after adjustment for baseline predictors of death (hazard ratio, 3.15; 95% confidence interval, 2.83 to 3.50). Longer duration of HF hospitalization enhanced the risk of dying, as did repeat HF hospitalizations. Moreover, risk of death was highest within a month of discharge and then declined progressively over time, particularly for death resulting from HF progression and for sudden cardiac death. We observed a similar pattern of risk associated with all-cause hospitalization, although the magnitude was less than that with HF hospitalization. Conclusions— In patients with chronic HF, the risk of death is greatest in the early period after discharge after a hospitalization for HF and is directly related to the duration and frequency of HF hospitalizations. These findings suggest a role for increased surveillance in the early postdischarge period of greatest vulnerability after an HF admission.
Treatment of orthopaedic tuberculosis.
Authors: D L Griffiths
Journal: BMJ (1979)

the bacteriological findings correlate well with those in that condition.The normal cell count in the CSF is rare in tuberculosis of the central nervous system but may occur.'-3We think that a positive culture for M tuberculosis might be a more common finding, were one to look for it, and that the possible tuberculous nature of meningitis should not be discarded because of benign presentation only.