tbuckley/cabot-search huggingface dataset:
<i>In Vitro</i>Sensitivity of CLL Cells to Fludarabine May Be Modulated by the Stimulation of Toll-like Receptors
Authors: Eleonora Fonte, Benedetta Apollonio, Lydia Scarfò, Pamela Ranghetti, Claudia Fazi, Paolo Ghia, Federico Caligaris-Cappio, Marta Muzio
Journal: Clinical Cancer Research (2012)

The emerging role of Toll-like receptors (TLR) in the pathogenesis of chronic lymphocytic leukemia (CLL) led us to ask whether TLR stimulation may protect CLL cells from drug-induced apoptosis.We cultured in vitro malignant B cells freshly isolated from 44 patients with CLLs in the presence or the absence of different concentrations of fludarabine before or after 24-hour TLR stimulation with specific ligands and evaluated cell viability, apoptosis, and molecular pathways involved.Heterogeneity was observed among samples. In leukemic cells from patients bearing adverse prognostic factors, TLR stimulation caused a significant increase of protection to fludarabine treatment, whereas this did not occur in the cells from patients with good prognosis. To identify novel molecular mechanisms accounting for the dichotomy of response between the two groups of patients, we conducted an apoptosis gene expression profile on leukemic cells either unstimulated or stimulated with TLR9 ligand. Strikingly, TLR9 stimulation specifically upregulated the expression of lymphotoxin-α in cells where an increased protection to fludarabine treatment was observed. Also, the expression of miR-155-3p was significantly increased after stimulation of distinct TLR in cells where fludarabine treatment was less effective.These results suggest that at least in a proportion of patients, in vitro sensitivity to fludarabine may be modulated by the stimulation of TLR, likely mimicking microenvironmental signals occurring in vivo.
Cysteine- rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients’ prognosis
Authors: Samir Al Bashir, Mohammed Alshalalfa, Samar A Hegazy, Michael Dolph, Bryan Donnelly, Tarek A Bismar
Journal: Journal of Hematology & Oncology (2014)

Cysteine- rich secretory protein 3 (CRISP3) prognostic significance in prostate cancer (PCA) has generated mixed result. Herein, we investigated and independently validated CRISP3 expression in relation to ERG and PTEN genomic aberrations and clinical outcome. CRISP3 protein expression was examined by immunohistochemistry using a cohort of patients with localized PCA (n = 215) and castration resistant PCA (CRPC) (n = 46). The Memorial Sloan Kettering (MSKCC) and Swedish cohorts were used for prognostic validation. Results showed, CRISP3 protein intensity to be significantly associated with neoplastic epithelium, being highest in CRPC vs. benign prostate tissue (p < 0.0001), but was not related to Gleason score (GS). CRISP3 mRNA was significantly associated with higher GS (p = 0.022 in MSKCC, p = 1.1e-4 in Swedish). Significant association between CRISP3 expression and clinical outcome was documented at the mRNA but not the protein expression levels. CRISP3 mRNA expression was related to biochemical recurrence in the MSKCC (p = 0.038) and lethal disease in the Swedish cohort (p = 0.0086) and retained its prognostic value in the subgroup of patients with GS 6 & 7. Furthermore, CRISP3 protein and mRNA expression was significantly associated with positive ERG status and with PTEN deletions. Functional biology analysis documented phenylalanine metabolism as the most significant pathway governing high CRISP3 and ERG expression in this subtype of PCA. In conclusion, the combined status of CRISP3, ERG and PTEN define a molecular subtype of PCA with poorest and lethal outcome. Assessing their combined value may be of added value in stratifying patients into different prognostic groups and identify those with poorest clinical outcome.
Pioneers in AIDS Care — Reflections on the Epidemic's Early Years
Authors: Ronald Bayer, Gerald M. Oppenheimer
Journal: New England Journal of Medicine (2006)

In July, 17 doctors gathered in New York to commemorate the 25th anniversary of the first reported AIDS cases. They listened to an oral history documenting the U.S. epidemic. Ronald Bayer and Gerald Oppenheimer discuss the July meeting, the shared memories of the darkest years, the exhilaration of the first prospects for effective treatment, and concern about who will step in to care for future patients.
Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria
Authors: Michael L. Merchant, Bruce A. Perkins, Grzegorz M. Boratyn, Linda H. Ficociello, Daniel W. Wilkey, Michelle T. Barati, Clinton C. Bertram, Grier P. Page, Brad H. Rovin, James H. Warram, Andrzej S. Krolewski, Jon B. Klein
Journal: Journal of the American Society of Nephrology (2009)

One third of patients with type 1 diabetes and microalbuminuria experience an early, progressive decline in renal function that leads to advanced stages of chronic kidney disease and ESRD. We hypothesized that the urinary proteome may distinguish between stable renal function and early renal function decline among patients with type 1 diabetes and microalbuminuria. We followed patients with normal renal function and microalbuminuria for 10 to 12 yr and classified them into case patients (n = 21) with progressive early renal function decline and control subjects (n = 40) with stable renal function. Using liquid chromatography matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we identified three peptides that decreased in the urine of patients with early renal function decline [fragments of alpha1(IV) and alpha1(V) collagens and tenascin-X] and three peptides that increased (fragments of inositol pentakisphosphate 2-kinase, zona occludens 3, and FAT tumor suppressor 2). In renal biopsies from patients with early nephropathy from type 1 diabetes, we observed increased expression of inositol pentakisphosphate 2-kinase, which was present in granule-like cytoplasmic structures, and zona occludens 3. These results indicate that urinary peptide fragments reflect changes in expression of intact protein in the kidney, suggesting new potential mediators of diabetic nephropathy and candidate biomarkers for progressive renal function decline.
Role of the renin-angiotensin system in ventilator-induced lung injury: an in vivo study in a rat model
Authors: J.-S. Jerng, Y.-C. Hsu, H.-D. Wu, H.-Z. Pan, H.-C. Wang, C.-T. Shun, C.-J. Yu, P.-C. Yang
Journal: Thorax (2007)

<b>Background:</b> Injurious mechanical ventilation can cause a pro-inflammatory reaction in the lungs. Recent evidence suggests an association of the renin-angiotensin system (RAS) with lung inflammation. A study was undertaken to investigate the pathogenic role of the RAS in ventilator-induced lung injury (VILI) and to determine whether VILI can be attenuated by angiotensin converting enzyme (ACE) inhibition. <b>Methods:</b> Male Sprague-Dawley rats were mechanically ventilated for 4 h with low (7 ml/kg) or high (40 ml/kg) tidal volumes; non-ventilated rats were used as controls. Lung injury and inflammation were measured by the lung injury score, protein leakage, myeloperoxidase activity, pro-inflammatory cytokine levels and nuclear factor (NF)-κB activity. Expression of the RAS components was also assessed. Some rats were pretreated with the ACE inhibitor captopril (10 mg/kg) for 3 days or received a concomitant infusion with losartan or PD123319 (type 1 or type 2 angiotensin II receptor antagonist) during mechanical ventilation to assess possible protective effects on VILI. <b>Results:</b> In the high-volume group (n = 6) the lung injury score, bronchoalveolar lavage fluid protein concentration, pro-inflammatory cytokines and NF-κB activities were significantly increased compared with controls (n = 6). Lung tissue angiotensin II levels and mRNA levels of angiotensinogen and type 1 and type 2 angiotensin II receptors were also significantly increased in the high-volume group. Pretreatment with captopril or concomitant infusion with losartan or PD123319 in the high-volume group attenuated the lung injury and inflammation (n = 6 for each group). <b>Conclusions:</b> The RAS is involved in the pathogenesis of ventilator-induced lung injury. ACE inhibitor or angiotensin receptor antagonists can attenuate VILI in this rat model.
The Steal Syndromes
Authors: J F Toole, C P McGraw
Journal: Annual Review of Medicine (1975)

Blood can be stolen from almost any vascular bed and redistributed. The external carotid artery can steal from cerebral structures when occlusion of the common carotid artery proximal to the bifurcation causes reversal of flow through the internal carotid artery (13, 45, 46). The external carotid artery has also been shown to steal blood flow from the vertebral artery distribution (13, 74). Double steals involving both the subclavian and external carotid arteries are seen in 1 to 2% of patients (13, 46). There is also the "triple steal syndrome" wherein both subclavian arteries and one external carotid artery are involved (14).
Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells.
Authors: A Moretta, S Sivori, M Vitale, D Pende, L Morelli, R Augugliaro, C Bottino, L Moretta
Journal: The Journal of Experimental Medicine (1995)

The natural killer (NK) cell-specific p58 molecules EB6 and GL183 have been shown to represent the putative surface receptors for two distinct groups of human histocompatibility leukocyte antigen (HLA) C alleles. Interaction between p58 receptors and class I molecules expressed on target cells results in inhibition of the NK-mediated cytolytic activity and thus in target cell protection. In the present study, we show that EB6 molecules may also act as receptors mediating NK cell triggering. Activatory EB6 molecules were found to be confined only to certain donors. Moreover, in these donors, only a fraction of EB6+ NK clones expressed the activatory form of EB6 molecules, while the remaining clones expressed the conventional inhibitory form. Biochemical analysis of the activatory EB6 molecules revealed a molecular mass of approximately 50 kD (p50), thus differing from the 58-kD inhibitory form. This difference was not due to differential glycosylation of the same protein, as revealed by deglycosylation experiments of isolated EB6 molecules. Treatment of purified p58 or p50/EB6 molecules with proteolytic enzymes, including V8-protease, chymotrypsin, and papain, showed only minor differences in the resulting peptides. Treatment with pepsin followed by two-dimensional peptide mapping demonstrated that, although the majority of peptides migrated in identical positions, differences between the two forms could be detected for at least one major peptide. Anti-EB6 monoclonal antibody (mAb)-mediated cross-linking of p50 molecules was required to trigger the cytolytic activity and the intracellular calcium ([Ca+2]i) increases in appropriate NK clones. Likewise, mAb-mediated cross linking of the p58 EB6 molecules was needed to inhibit the cytolytic activity; however, in this case, no [Ca+2]i increases could be detected. In NK clones expressing the inhibitory p58 EB6 receptors, soluble anti-EB6 mAb prevented recognition of protective Cw4 molecules and reconstituted target cell lysis. In contrast, in clones expressing the activatory p50/EB6 receptor, EB6 masking frequently resulted in partial inhibition of the cytolytic activity against Cw4+ target cells. Therefore, it appears that NK clones expressing the p50/EB6 receptors are induced to lyse Cw4+ target cells upon specific interaction with Cw4 molecules. This concept was further substantiated by experiments in which target cells were represented by the HLA-negative LCL721.221 cell line transfected with the Cw4 allele. Phenotypic and functional analysis of a large number of NK clones showed that clones expressing the activatory p50/EB6 molecules consistently coexpressed inhibitory receptors for other HLA class I alleles.(ABSTRACT TRUNCATED AT 400 WORDS)
The use of carboxymethylcellulose gel to increase non-viral gene transfer in mouse airways
Authors: Uta Griesenbach, Cuixiang Meng, Raymond Farley, Marguerite Y. Wasowicz, Felix M. Munkonge, Mario Chan, Charlotte Stoneham, Stephanie G. Sumner-Jones, Ian A. Pringle, Deborah R. Gill, Stephen C. Hyde, Barbara Stevenson, Emma Holder, Hiroshi Ban, Mamoru Hasegawa, Seng H. Cheng, Ronald K. Scheule, Patrick L. Sinn, Paul B. McCray, Eric W.F.W. Alton
Journal: Biomaterials (2009)
Health and human rights
Authors: J. M Mann
Journal: BMJ (1996)

When the World Health Organisation redefined health as “a state of complete physical, mental and social well-being”1 it not only expanded health far beyond medicine, it openly acknowledged the vast accumulated knowledge about the central role of societal determinants of population health. Despite the public's belief to the contrary, medical care is a relatively minor, albeit important, contributor to health,2 far outweighed by societal factors, of which social class has been the most extensively studied.3 4

In 1988, a seminal report by the United States Institute of Medicine defined the mission of public health as “ensuring the conditions in which people can be healthy.”4 In turn, this required those working in public health to consider the societal nature of these essential conditions in which people could achieve the highest attainable standard of physical, mental, and social wellbeing. Paradoxically, the discipline of public health has generally ignored the societal roots of health in favour of medical interventions, which operate further downstream. For example, public health efforts at preventing and …
Different Ages of Onset in Varieties of Phobia
Authors: I. M. MARKS, M. G. GELDER
Journal: American Journal of Psychiatry (1966)

One hundred and thirty-nine adult phobic patients presenting for treatment were subdivided into four groups with phobias of: I) animals and insects; II) specific situations (e.g., heights, thunder); III) social situations; and IV) agoraphobia. All four groups first sought treatment at comparable ages in adult life. However, the onset age of phobias differed between groups: hardly any phobias of animals and insects had started after age five, while most phobias of the other varieties started after age ten. This suggests a facilitatory period in early childhood for the acquisition of certain fears. This different onset age of animal phobias was accompanied by other differentiating features: circumscribed symptoms, continuous course, and a better response to behavior therapy despite longer duration of symptoms.
Hepatic Graft Versus Host Disease: A Study of the Predictive Value of Liver Biopsy in Diagnosis
Authors: Dale C. Snover, Sally A. Weisdorf, Norma K. Ramsay, Philip Mcglave, John H. Kersey
Journal: Hepatology (1984)

Ninety-six liver biopsies [32 bone marrow transplant (BMT), 7 pre-BMT, and 57 non-BMT] are reviewed for histological evidence of graft versus host disease (GVHD), based on bile duct atypia and related inflammatory changes. In addition, the presence of cholestasis, piecemeal necrosis, and attachment of lymphocytes to vascular endothelium (endothelialitis) are evaluated. The 57 non-BMT biopsies include examples of viral hepatitis (acute and chronic), nonviral chronic hepatitis, extrahepatic biliary obstruction, cytomegalovirus hepatitis, primary biliary cirrhosis, and orthotopic liver transplant rejection. Although the sensitivity of bile duct damage as an indicator of GVHD appears high (only one probable false negative was noted), there is considerable overlap between the changes of GVHD and occasional cases of acute and chronic hepatitis and extrahepatic biliary obstruction. Nine of the 57 non-BMT biopsies (15%) were felt to be consistent with GVHD and represent “false positives”. Despite this relative lack of specificity, analysis of several features in combination provided clues to improve accuracy of diagnosis. The findings of extensive bile duct damage with minimal inflammatory changes is characteristic of GVHD. Possibly more predictive is the presence of endothelialitis of portal or central veins, which was seen in only three non-BMT biopsies, being present in eight cases of GVHD.
Junior Staff Representation
Authors: J. H. Wetherill
Journal: BMJ (1967)

Fetal septal neurons were grown in vitro under glass coverslips. This sandwich culture method significantly increased general neuronal survival, reduced glial proliferation, and permitted the removal of serum from the growth medium after 5 d in vitro. Thereafter, a simple, and completely defined, medium was used, and the effects of NGF, NGF withdrawal, and protein synthesis inhibition were examined on septal cholinergic neurons. NGF added to septal cultures at the time of plating resulted in a threefold increase in the number of cholinergic neurons seen at 14 d in vitro but had no effect on the survival of non- cholinergic cells. Cholinergic neurons identified by staining for AChE, ChAT, and p75NGFR could be maintained in serum-free, NGF-supplemented medium for over 40 d. When NGF was removed and NGF antibodies added to 14-d-old cultures, less than 30% of cholinergic neurons survived a further 4 d, but when NGF was similarly withdrawn from 35-d-old cultures, over 75% of cholinergic neurons survived. Reapplication of NGF after 3 but not after 12 or more hours of NGF withdrawal from 14-d- old cultures prevented the death of most cholinergic neurons. When NGF was withdrawn from 14-d-old cultures in the presence of the protein synthesis inhibitor cycloheximide, over 75% of the cholinergic neurons survived. These findings suggest that septal cholinergic neurons are dependent on NGF for survival only during a critical period of development and that growth factor-regulated developmental cell death may occur in CNS neurons by activation of programmed cell death requiring protein synthesis.
Insulin Treatment and Type 1 Diabetes Topics
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2006)

This is the fifth in a series of articles on presentations at the American Diabetes Association Annual Meeting, San Diego, California, 10–14 June 2005.

### Basal insulin.

Malcolm Nattrass (Birmingham, U.K.) discussed basal insulin analogs, noting that the ideal approach will lead to “a flat profile that is reproducible.” The development of basal insulin began with protamine zinc insulin in 1936, followed by NPH insulin in 1946 and zinc insulins lente, semilente, and ultralente in 1951. All of these preparations have high variability, making them less than optimal for treatment. Natrass reviewed studies of persons given four injections of 0.4 units/kg NPH in the thigh, with measurement of the glucose infusion rate required to maintain euglycemia. Great variability in biologic activity was shown. Early strategies pursued with insulin analogs included changes in the isoelectric point leading to precipitation at pH 7.4 with NovoSol Basal (1) and strengthening hexamer formation with Co(III)-hexamer insulin. Neither strategy led to successful development of a commercial product. Subsequent research led to insulin glargine, which is stable and soluble in acidic solution, precipitating following injection into subcutaneous tissues. Compared with NPH, there is major improvement in variability comparable to that with continuous subcutaneous insulin infusion (CSII) and a considerably “flatter” action profile than seen with NPH. Another method involves acylation of the insulin molecule with hydrophobic residues. Insulin detemir has a myristic acid fatty acid side chain that strengthens self-association, leading to increased hexamer formation and to albumin binding at the injection site and in the circulation. The binding to albumin may buffer insulin action.

Nattrass reviewed a number of studies of glargine and of detemir. In a study of 619 persons with type 1 diabetes, insulin glargine given at bedtime was associated with lower fasting glucose and with lower variability in fasting glucose level than NPH insulin given …
Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life
Authors: Tye E. Arbuckle, Russ Hauser, Shanna H. Swan, Catherine S. Mao, Matthew P. Longnecker, Katharina M. Main, Robin M. Whyatt, Pauline Mendola, Melissa Legrand, Joanne Rovet, Christine Till, Mike Wade, John Jarrell, Stephen Matthews, Guy Van Vliet, Carl-Gustaf Bornehag, Roger Mieusset
Journal: Environmental Health Perspectives (2008)

An international workshop titled "Assessing Endocrine-Related Endpoints within the First Years of Life" was held 30 April-1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions.
Cytomegalovirus infection enhances the immune response to influenza
Authors: David Furman, Vladimir Jojic, Shalini Sharma, Shai S. Shen-Orr, Cesar J. L. Angel, Suna Onengut-Gumuscu, Brian A. Kidd, Holden T. Maecker, Patrick Concannon, Cornelia L. Dekker, Paul G. Thomas, Mark M. Davis
Journal: Science Translational Medicine (2015)

Cytomegalovirus infection of young adult humans and mice enhances immune responses to influenza.
IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease
Authors: Monica Castellucci, Marzia Rossato, Federica Calzetti, Nicola Tamassia, Stefano Zeminian, Marco A Cassatella, Flavia Bazzoni
Journal: Journal of Allergy and Clinical Immunology (2015)