tbuckley/cabot-search huggingface dataset:
Phase I Clinical and Magnetic Resonance Imaging Study of the Vascular Agent NGR-hTNF in Patients with Advanced Cancers (European Organization for Research and Treatment of Cancer Study 16041)
Authors: Hanneke W.M. van Laarhoven, Walter Fiedler, Ingrid M.E. Desar, Jack J.A. van Asten, Sandrine Marréaud, Denis Lacombe, Anne-Sophie Govaerts, Jan Bogaerts, Peter Lasch, Johanna N.H. Timmer-Bonte, Antonio Lambiase, Claudio Bordignon, Cornelis J.A. Punt, Arend Heerschap, Carla M.L. van Herpen
Journal: Clinical Cancer Research (2010)

This phase I trial investigating the vascular targeting agent NGR-hTNF aimed to determine the (a) dose-limiting toxicities, (b) maximum tolerated dose (MTD), (c) pharmacokinetics and pharmacodynamics, (d) vascular response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (e) preliminary clinical activity in solid tumors.NGR-hTNF was administered once every 3 weeks by a 20- to 60-minute i.v. infusion to cohorts of three to six patients with solid tumors in escalating doses. Pharmacokinetic and pharmacodynamic analyses in blood were done during the first four cycles. DCE-MRI was done in cycle 1 at baseline and 2 hours after the start of the infusion.Sixty-nine patients received a total of 201 cycles of NGR-hTNF (0.2-60 microg/m(2)). Rigors and fever were the most frequently observed toxicities. Four dose-limiting toxicities were observed (at doses of 1.3, 8.1, and 60 microg/m(2)), of which three were infusion related. The MTD was 45 microg/m(2). The mean apparent terminal half-life ranged from 0.963 to 2.08 hours. DCE-MRI results of tumors showed a vascular response to NGR-hTNF. No objective responses were observed, but 27 patients showed stable disease with a median duration of 12 weeks.NGR-hTNF was well tolerated. The MTD was 45 microg/m(2) administered in 1 hour once every 3 weeks. DCE-MRI results showed the antivascular effect of NGR-hTNF. These findings call for further research for defining the optimal biological dose and clinical activity of NGR-hTNF as a single agent or in combination with cytotoxic drugs.
P31 Assessing the effectiveness of tuberculosis (TB) screening in new entrant healthcare workers using different time cut-offs to define high risk individuals: Abstract P31 Table 1.
Authors: R Morton, K Bintley, Z Alexander, V Kahr
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> NICE (2011) and the Department of Health (2007) provide guidance for occupational health departments for TB clearance in healthcare workers. Previous work from the London Consortium of Occupational Health Providers (LCOHPS) shows a marked variation in practice, notably in the criteria for defining high risk individuals. The length of time in the UK for an individual from a high TB endemic area (defined as an incidence of 40 per 100,000 or greater) to be considered as low risk ranges from 6 months to &gt;5 years. We performed a retrospective study of new trust employees to see if changing the definition of a high risk individual would impact on the effectiveness of our screening programme. <h3>Methods</h3> We performed a retrospective study of 40 new employees at our trust between 2008 and 2012. Cases were selected on the basis of a positive QuantiFERON-TB Gold test at occupational health screening. Demographic data, including date of UK entry, were collected and analysed. <h3>Results</h3> Results are summarised in Table 1. <h3>Conclusions</h3> Changing the definition of a high risk individual by reducing the cut-off time since entry to the UK may have both financial and time-saving consequences. However, our data show that a significant proportion of healthcare workers with latent TB infection, and in some cases active TB infection, would be missed by reducing the cut-off to 1 year. Screening of healthcare workers is an important aspect in the prevention and control of TB. Reducing the effectiveness of this screening exposes patients to increased risk. In view of these data, we would not recommend reducing the cut-off time for the definition of a high risk individual to less than 5 years.
Effects of Acetaldehyde on Cell Regeneration and Differentiation of the Upper Gastrointestinal Tract Mucosa
Authors: N. Homann, T. Koivisto, T. Nosova, K. Jokelainen, M. Salaspuro, P. Karkkainen
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: The tumor-promoting effect of ethanol on cancer of the upper respiratory—digestive tract is not well understood. Although ethanol itself is not carcinogenic, the first product of ethanol metabolism—acetaldehyde—is. Acetaldehyde can be produced from ethanol by oral bacteria, and high concentrations have been observed in human saliva after ethanol consumption. The purpose of this study was to investigate whether acetaldehyde administered orally to rats induces altered differentiation and proliferation in the animals' upper gastrointestinal tracts. Methods: Twenty Wistar rats were given either water containing acetaldehyde at a concentration of 120 m M or tap water to drink for 8 months. Tissue specimens were then taken from the tongue, epiglottis, and forestomach of each animal and immunohistochemically stained for markers of cellular proliferation (Ki67 nuclear antigen) or differentiation (cytokeratins 1, 4, 10, 11, 14, and 19). The mean epithelial thickness of each sample was measured via light microscopy, using an eyepiece containing grid lines. Differences between the control and acetaldehyde-treated groups were analyzed by use of the unpaired Student's t test. All reported P values are two-sided. Results: Although no tumors were observed, staining for cytokeratins 4 and 14 revealed an enlarged basal layer of squamous epithelia in the rats receiving acetaldehyde. In these animals, cell proliferation was significantly greater than that observed in the control animals for samples from the tongue ( P <.0001), epiglottis ( P <.001), and forestomach ( P <.0001). In addition, the epithelia from acetaldehyde-treated rats were significantly thicker than in epithelia from control animals ( P <.05 for all three sites). Conclusions: Acetaldehyde, administered orally to rats, can cause hyperplastic and hyperproliferative changes in epithelia of the upper gastrointestinal tract. This finding suggests that microbially produced acetaldehyde in saliva may explain the tumor-promoting effect of ethanol on these epithelia.
Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells
Authors: Mayumi Tamada, Osamu Nagano, Seiji Tateyama, Mitsuyo Ohmura, Toshifumi Yae, Takatsugu Ishimoto, Eiji Sugihara, Nobuyuki Onishi, Takehiro Yamamoto, Hiroshi Yanagawa, Makoto Suematsu, Hideyuki Saya
Journal: Cancer Research (2012)

Abstract An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance. Cancer Res; 72(6); 1438–48. ©2012 AACR.
Opportunistic agents in bronchoalveolar lavage in 99 HIV seropositive patients
Authors: S Durand-Amat, G Zalcman, MC Mazeron, C Sarfati, B Beauvais, F Gerber, Y Perol, A Hirsch
Journal: European Respiratory Journal (1990)

During a ten month period, 117 fibreoptic bronchoscopies and bronchoalveolar lavages (BAL) were performed in human immunodeficiency virus (HIV) infected patients suspected of having opportunistic pulmonary infections. The BAL were classified into 3 groups, according to clinical manifestations related to HIV infection at the time of fibreoptic bronchoscopy: pre-acquired immunodeficiency syndrome (AIDS) (n = 54), AIDS with Kaposi's sarcoma (n = 37), AIDS without Kaposi's sarcoma (n = 26). On chest X-ray, diffuse infiltrates were most common (54%), followed by normal X-rays (24%) and localized infiltrates (18%). Amongst the 117 BAL, 68 (58%) yielded at least one opportunistic agent. In 28 BAL performed for pulmonary signs or unexplained fever with normal chest X-rays, one or several opportunistic agents were isolated in 17 samples of BAL fluid. The most frequently identified opportunistic agents were Pneumocystis carinii (in 38% of BAL) and cytomegalovirus (35%); these were associated in 17% of BAL. There was no statistically significant difference in opportunistic agents among the 3 groups of BAL (pre-AIDS, AIDS with Kaposi's sarcoma, AIDS without Kaposi's sarcoma). In particular, cytomegalovirus was found in BAL with the same frequency in these 3 groups.
Defence Societies and Disciplinary Actions
Authors: J. L. Taylor
Journal: BMJ (1972)

This procedure would have two advan- tages.The first is that it would overcome many of the administrative difficulties, both on the ward and in the laboratory, which arise from the necessity of sending a plasma sample and request card to the laboratory on one day and the 24-hour urine sample with a second request card on the following day.If the plasma is taken when the collec- tion is completed, both specimens can be sent with a single request card.The second, perhaps less important, advantage is that with this procedure the change in creatinine clearance will be greater than with the conventional method should the plasma creatinine be rising or falling during the period of the urine collection.For example, if renal function were deteriorating and plasma creatinine rising the creatinine clear- ance would be lower if the plasma is taken at the end of the urine collection than if it is taken in the middle.There is no doubt that clinical biochemistry laboratories would welcome this change in procedure, and it appears to have no clinical disadvantages.-Weare, etc.,
Coordinate Loss of <i>MAP3K7</i> and <i>CHD1</i> Promotes Aggressive Prostate Cancer
Authors: Lindsey Ulkus Rodrigues, Leah Rider, Cera Nieto, Lina Romero, Anis Karimpour-Fard, Massimo Loda, M. Scott Lucia, Min Wu, Lihong Shi, Adela Cimic, S. Joseph Sirintrapun, Rosalie Nolley, Colton Pac, Haitao Chen, Donna M. Peehl, Jianfeng Xu, Wennuan Liu, James C. Costello, Scott D. Cramer
Journal: Cancer Research (2015)

Abstract Prostate cancer subtypes are poorly defined and functional validation of drivers of ETS rearrangement–negative prostate cancer has not been conducted. Here, we identified an ETS− subtype of aggressive prostate cancer (ERG−MAP3K7delCHD1del) and used a novel developmental model and a cell line xenograft model to show that cosuppression of MAP3K7 and CHD1 expression promotes aggressive disease. Analyses of publicly available prostate cancer datasets revealed that MAP3K7 and CHD1 were significantly codeleted in 10% to 20% of localized tumors and combined loss correlated with poor disease-free survival. To evaluate the functional impact of dual MAP3K7–CHD1 loss, we suppressed Map3k7 and/or Chd1 expression in mouse prostate epithelial progenitor/stem cells (PrP/SC) and performed tissue recombination experiments in vivo. Dual shMap3k7–shChd1 PrP/SC recombinants displayed massive glandular atypia with regions of prostatic intraepithelial neoplasia and carcinoma apparent. Combined Map3k7–Chd1 suppression greatly disrupted normal prostatic lineage differentiation; dual recombinants displayed significant androgen receptor loss, increased neuroendocrine differentiation, and increased neural differentiation. Clinical samples with dual MAP3K7–CHD1 loss also displayed neuroendocrine and neural characteristics. In addition, dual Map3k7–Chd1 suppression promoted E-cadherin loss and mucin production in recombinants. MAP3K7 and CHD1 protein loss also correlated with Gleason grade and E-cadherin loss in clinical samples. To further validate the phenotype observed in the PrP/SC model, we suppressed MAP3K7 and/or CHD1 expression in LNCaP prostate cancer cells. Dual shMAP3K7–shCHD1 LNCaP xenografts displayed increased tumor growth and decreased survival compared with shControl, shMAP3K7, and shCHD1 xenografts. Collectively, these data identify coordinate loss of MAP3K7 and CHD1 as a unique driver of aggressive prostate cancer development. Cancer Res; 75(6); 1021–34. ©2015 AACR.
Enhancement of the immune response to hepatitis B surface antigen. In vivo administration of antiidiotype induces anti-HBs that expresses a similar idiotype.
Authors: R C Kennedy, G R Dreesman
Journal: The Journal of Experimental Medicine (1984)

BALB/c mice receiving antiidiotype antibodies before the injection of hepatitis B surface antigen (HBsAg) generated an enhanced anti-HBs response. Mice given antiidiotype antibodies in a soluble form induced predominantly IgM anti-HBs, whereas alum-precipitated antiidiotype produced primarily IgG anti-HBs. Injection of antiidiotype antibodies alone induced anti-HBs that inhibited a common interspecies anti-HBs idiotype-antiidiotype reaction and recognized the group-specific determinant of HBsAg. These data support the view that antiidiotype antibodies may modulate the immune response to an infectious viral agent.
KSHV INFECTION AND THE PATHOGENESIS OF KAPOSI'S SARCOMA
Authors: Don Ganem
Journal: Annual Review of Pathology Mechanisms of Disease (2006)

Kaposi's sarcoma (KS) has long been suspected of having an infectious etiology on the basis of its unusual epidemiology, histopathology, and natural history. Nearly a decade ago, a novel herpesviral genome was discovered in KS biopsies, and since that time strong epidemiologic evidence has accumulated correlating infection with this KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) with the development of the disease. Here we review the evidence linking KSHV infection to KS risk and discuss current notions of how KSHV gene expression promotes the development of this remarkable neoplasm. These studies show that both latent and lytic viral replicative cycles contribute significantly—but differently—to KS development. The studies also highlight mechanistic differences between oncogenesis caused by KSHV and that caused by its distant relative Epstein-Barr virus.
Can inactivated Mycobacterium vaccae vaccine help protect HIV positive patients against tuberculosis?
Authors: V L C White
Journal: Thorax (2003)

Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.
Analysis of Cytokine Profiles in Patients With Human Papillomavirus-Associated Neoplasms
Authors: T.- C. Wu, R. J. Kurman
Journal: JNCI Journal of the National Cancer Institute (1997)

Two nuclear signalling pathways for vitamin D. Nature 1993;361: 657-60. (47) Elstner E, Linker-Israeli M, Umiel T, Le J, Grillier I, Said J, et al. Combination of a potent 20-epi-vitamin D3 analogue (KH 1060) with 9-cisretinoic acid irreversibly inhibits clonal growth, decreases bcl-2 expression, and induces apoptosis in HL-60 leukemic cells. Cancer Res 1996;56: 3570-6. (48) Elstner E, Linker-Israeli M, Le J, Umiel T, Michl P, Said JW, et al. Synergistic decrease of clonal proliferation, induction of differentiation and apoptosis of APL cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid. J Clin Invest. In press. (49) Yoshinaga SK, Peterson CL, Herskowitz I, Yamanoto KR. Roles of SWI1, SWI2, and SWI3 proteins for transcriptional enhancement by steroid receptors. Science 1992;258:1598-604. (50) Onate SA, Tsai SY, Tsai MJ, O’Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354-7.
Pharmacology of gap junctions in the cardiovascular system
Authors: S Dhein
Journal: Cardiovascular Research (2004)

Gap junction channels provide the basis for intercellular communication and play an important physiological role in the cardiovascular system for maintenance of the normal cardiac rhythm, regulation of vascular tone, endothelial function and myoendothelial interaction as well as for metabolic interchange between the cells. Thus, pharmacological influence on these channels might help to elucidate their role in physiology and pathophysiology and might reveal new therapeutic approaches. The gap junction conductance between two cells is defined by the number of channels, the single channel conductance and the mean open and closed time. In principle, it is possible pharmacologically to induce closing of the channels, to change preferred single channel conductance, to open channels (or to keep them open), and to regulate the expression, synthesis, assembly and degradation of the channels thereby controlling the number of channels. This review describes the various substances affecting these parameters and outlines the possible pharmacological use of such drugs.
Commentary on the 2014 BP Guidelines from the Panel Appointed to the Eighth Joint National Committee (JNC 8)
Authors: Efrain Reisin, Raymond C. Harris, Mahboob Rahman
Journal: Journal of the American Society of Nephrology (2014)

The recently published article "2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)" (James et al., JAMA 311: 507-520, 2014) has generated considerable controversy. In this commentary, we evaluate the document and compare the recommendations contained within it with those of the JNC 7 and other national and international guidelines. The evidence quality rating approach followed by the article "2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)" (James et al., JAMA 311: 507-520, 2014) disqualified nearly 98% of previous studies from review; as a result, some of the key recommendations were on the basis of expert opinion alone. We are especially concerned that the recommendation to raise the systolic/diastolic BP levels at which treatment is initiated to ≥150/≥90 mmHg in adults≥60 years old may affect cardiovascular and renal health in these patients. Additionally, we recommend that hypertension guidelines should be updated every 3-4 years with a fresh approach to the definition of target BP levels, the use of modern technology in the diagnosis of hypertension, and the treatment of hypertension in special populations not addressed in earlier guidelines.
Results HEED Belgium – Health-related quality of life in patients by COPD severity within primary care in Belgium
Authors: Guy Brusselle, Paul Jones, Lukasz Adamek, Norbert Banik, Alex Mehuys
Journal: European Respiratory Journal (2011)

Pan-European data on health status in COPD are scarce. The purpose of the HEED study was to evaluate the health status from a primary care COPD population in seven European Countries (Jones P. et al. Health-related quality of life in patients by COPD severity within primary care in Europe. Respiratory Medicine 2010).

We present here the Belgian results of this Pan-European survey.

This cross-sectional epidemiological study in a primary care setting evaluated health status in 394 COPD patients by Belgian primary care physicians using the St George's Respiratory Questionnaire-C (SGRQ) and the COPD Assessment test (CAT). The Health-related Quality of Life (HRQoL) scores by GOLD stage, using both the SGRQ and the CAT, are shown in Table 1.

View this table:

Table 1. HRQoL Scores by GOLD Stage





HRQoL scores deteriorated as GOLD stage advanced, and the CAT score and the SGRQ score correlated closely (correlation coefficient of 0,8462; p < 0,0001.

![Figure][1] 



Conclusion: Although both SGRQ total score and CAT score correlate significantly with COPD severity and with each other, there is important heterogeneity in both HRQoL scores among COPD patients per GOLD stage.

 [1]: pending:yes
Deoxycorticosterone Suppresses the Effects of Losartan in Nitric Oxide—Deficient Hypertensive Rats
Authors: MARIA C. DE GRACIA, ANTONIO OSUNA, FRANCISCO O'VALLE, RAIMUNDO G. DEL MORAL, ROSEMARY WANGENSTEEN, CIPRIANO GARCIA DEL RIO, FELIX VARGAS
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Chronic inhibition of the renin angiotensin system prevents increased BP and renal injury in N G -nitro-L-arginine methyl ester (L-NAME) hypertension. However, a relationship between plasma renin activity and the protective effect of chronic angiotensin II (Ang II) blockade has not been established. With this background, this study was undertaken to evaluate how the chronic administration of deoxycortisone acetate (DOCA) modifies the effects of losartan on BP, renal injury, and other variables in L-NAME hypertensive rats. The following groups were used: Control, DOCA, L-NAME, L-NAME + losartan, L-NAME + DOCA, and L-NAME + DOCA + losartan. Tail systolic BP was measured twice a week. After 4-wk evolution, mean arterial pressure and metabolic, morphologic, and renal variables were measured. The final mean arterial pressure values were 116 ± 6 mmHg for control, 107 ± 2 mmHg for DOCA, 151 ± 5 mmHg for L-NAME, 123 ± 2 mmHg for L-NAME + losartan, 170 ± 3 mmHg for L-NAME + DOCA, and 171 ± 5.5 mmHg for L-NAME + DOCA + losartan. Losartan prevented microalbuminuria, hyaline arteriopathy, and glomerulosclerosis of L-NAME hypertension but was ineffective in L-NAME + DOCA—treated rats. Plasma protein was significantly reduced in the L-NAME + DOCA group when compared with control and L-NAME groups, whereas no significant differences were observed in the other groups. Plasma renin activity was suppressed in the DOCA (0.55 ± 0.2) and L-NAME + DOCA (0.60 ± 10.2) groups but unsuppressed in the L-NAME + DOCA + losartan group (5.8 ± 1). The conclusion is that DOCA blocks the preventive effect of losartan on the increased BP and renal injury of L-NAME hypertension, which suggests that DOCA transforms L-NAME hypertension into an Ang II—independent model of hypertension. These data also suggest that losartan prevents L-NAME hypertension by blocking the activity of systemic Ang II.