tbuckley/cabot-search huggingface dataset:
Diagnostic performance of a seven-marker serum protein biosignature for the diagnosis of active TB disease in African primary healthcare clinic attendees with signs and symptoms suggestive of TB
Authors: Novel N Chegou, Jayne S Sutherland, Stephanus Malherbe, Amelia C Crampin, Paul L A M Corstjens, Annemieke Geluk, Harriet Mayanja-Kizza, Andre G Loxton, Gian van der Spuy, Kim Stanley, Leigh A Kotzé, Marieta van der Vyver, Ida Rosenkrands, Martin Kidd, Paul D van Helden, Hazel M Dockrell, Tom H M Ottenhoff, Stefan H E Kaufmann, Gerhard Walzl
Journal: Thorax (2016)

<h3>Background</h3> User-friendly, rapid, inexpensive yet accurate TB diagnostic tools are urgently needed at points of care in resource-limited settings. We investigated host biomarkers detected in serum samples obtained from adults with signs and symptoms suggestive of TB at primary healthcare clinics in five African countries (Malawi, Namibia, South Africa, The Gambia and Uganda), for the diagnosis of TB disease. <h3>Methods</h3> We prospectively enrolled individuals presenting with symptoms warranting investigation for pulmonary TB, prior to assessment for TB disease. We evaluated 22 host protein biomarkers in stored serum samples using a multiplex cytokine platform. Using a pre-established diagnostic algorithm comprising of laboratory, clinical and radiological findings, participants were classified as either definite TB, probable TB, questionable TB status or non-pulmonary TB. <h3>Results</h3> Of the 716 participants enrolled, 185 were definite and 29 were probable TB cases, 6 had questionable TB disease status, whereas 487 had no evidence of TB. A seven-marker biosignature of C reactive protein, transthyretin, IFN-γ, complement factor H, apolipoprotein-A1, inducible protein 10 and serum amyloid A identified on a training sample set (n=491), diagnosed TB disease in the test set (n=210) with sensitivity of 93.8% (95% CI 84.0% to 98.0%), specificity of 73.3% (95% CI 65.2% to 80.1%), and positive and negative predictive values of 60.6% (95% CI 50.3% to 70.1%) and 96.4% (95% CI 90.5% to 98.8%), respectively, regardless of HIV infection status or study site. <h3>Conclusions</h3> We have identified a seven-marker host serum protein biosignature for the diagnosis of TB disease irrespective of HIV infection status or ethnicity in Africa. These results hold promise for the development of a field-friendly point-of-care screening test for pulmonary TB.
Imaging Flow Cytometry and Microfluidic Flow Assays Demonstrate Heterocellular Aggregation Of Immature Sickle Erythrocytes To Neutrophils Via Mac-1/VLA-4 Interactions
Authors: Venina Marcela Dominical, Leigh Samsel, Daiana Morelli Vital, James S Nichols, Vanessa Tonin Garrido, Sara T O Saad, Fernando Ferreira Costa, J. Philip McCoy, Nicola Conran, Gregory J. Kato
Journal: Blood (2013)
Changes in AIDS risk behaviors among homosexual male physicians and university students
Authors: D E Klein, G Sullivan, D L Wolcott, J Landsverk, S Namir, F I Fawzy
Journal: American Journal of Psychiatry (1987)

Two samples of homosexual men, 64 physicians and 58 university students, reported profound decreases in several sexual practices linked to transmission of acquired immune deficiency syndrome (AIDS). The physicians showed the greater reduction. When sociodemographic variables, health beliefs, feeling of control over outcome, mood, sexual interest before the AIDS epidemic, and medical care utilization were correlated with decrease and/or increase in AIDS risk behaviors, the clusters of variables most strongly correlated with change in risk behaviors differed between the physicians and students. Interventions designed to change behaviors in AIDS high-risk groups should be tailored for specific subgroups.
An amateur runner with hip pain and antalgic gait
Authors: Henry James Jonathon Hughes, Stefan Kluzek
Journal: BMJ (2016)

A 52 year old amateur runner who had increased his running distance over a short period of time presented to clinic with a 17 week history of hip pain associated with antalgic gait. He had no other symptoms or medical history of note and was not taking any drugs. His blood tests showed low testosterone levels only, and his DEXA (dual energy x ray absorptiometry) scan was normal. Pelvic radiography was performed (fig 1 …
Overexpression of S100A4 is associated with aggressiveness of endometrial adenocarcinoma
Authors: Ran Xie, David Loose, Gregory L. Shipley, Susu Xie, Russell Broaddus
Journal: Cancer Research (2005)

5582  Tumors of the endometrioid subtype comprise about 80% of all endometrial adenocarcinomas (EC). Myometrial invasion is one of the most important prognostic indicators for this histotype of endometrial cancer. However, the molecular determinants of myometrial invasion are poorly understood. In this study, we used 60-mer in situ synthesized oligonucleotide microarrays containing 18,716 different genes to analyze gene expression profiles in 5 cases of non-invasive (tumor confined to the endometrium) and 5 cases of invasive (more than 50% myometial invasion) grade 2 endometrial endometrioid adenocarcinoma (EEC) to identify differentially expressed genes that are associated with the myometrial invasion. After analysis of the microarray data, there was at least a 2-fold difference in expression between non-invasive and invasive EEC in 84 genes. The 77 genes up-regulated in invasive EEC were associated with the cellular activities known to be important in tumor invasion. Among them, several members of the S100A (S100A4, S100A6, S100A10, S100A11) and Annexin (ANXA1, ANXA2, ANXA11) families were consistently overexpressed in the invasive EEC. Using real-time quantitative PCR (RT-PCR), we validated the above candidate genes using a large set of EC (n=73) and normal endometrium (n=19). Only S100A4 was validated to be significantly overexpressed in the invasive EEC compared to the noninvasive EEC (P
Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells
Authors: Eva Billerbeck, Michiel C. Mommersteeg, Amir Shlomai, Jing W. Xiao, Linda Andrus, Ankit Bhatta, Koen Vercauteren, Eleftherios Michailidis, Marcus Dorner, Anuradha Krishnan, Michael R. Charlton, Luis Chiriboga, Charles M. Rice, Ype P. de Jong
Journal: Journal of Hepatology (2016)
Talimogene Laherparepvec for the Treatment of Advanced Melanoma
Authors: Patrick A. Ott, F. Stephen Hodi
Journal: Clinical Cancer Research (2016)

Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an "in situ vaccine" effect. Based on an increased durable response rate compared with granulocyte macrophage-colony stimulating factor in a randomized phase III trial, it was approved by the FDA for the treatment of melanoma metastatic to skin or lymph nodes. The drug is currently in clinical trials as monotherapy and in combination with immune-checkpoint inhibitors and radiotherapy in melanoma and other cancers. The mechanism of action, toxicity, and efficacy as well as its role in current clinical practice and potential future applications are reviewed. Clin Cancer Res; 22(13); 3127-31. ©2016 AACR.
Pharmacokinetic profile of fulvestrant 500 mg vs 250 mg: Results from the NEWEST study
Authors: I. Kuter, F. Sapunar, P. McCormack
Journal: Journal of Clinical Oncology (2008)

579 Background: Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors (NEWEST) is a randomized, phase II study comparing fulvestrant approved dose (AD; 250 mg/month) with a high-dose regimen (HD; 500 mg/month plus 500 mg on Day 14 of Month 1) as neoadjuvant therapy for postmenopausal women with newly diagnosed, estrogen receptor (ER)-positive, locally advanced breast cancer. In the primary analysis, fulvestrant HD compared with AD resulted in a statistically significant greater reduction in Ki67 labeling index (LI) as well as greater downregulation of both ER and progesterone receptor (PgR) expression. Here we report pharmacokinetic (PK) data from NEWEST. Methods: Core biopsies were taken at baseline, Wk 4 and at surgery (Wk 16), and assessed for changes in Ki67 LI, ER, and PgR expression (ER and PgR Intensity Score analyzed using ChromaVision™ Automated Cellular Imaging System). Blood samples for PK analysis were taken on Days 0, 28, 56, 84, and 112. An additional sample was taken between Days 6–10 (both groups) and Days 20–24 (HD group only). HPLC-MS and liquid-liquid extraction were used to determine plasma fulvestrant levels. Plasma samples were analyzed using NONMEM, and Bayesian PK parameter estimates were used to determine Cmax and AUC0–28 days at Wks 4 and 16. Correlations between fulvestrant plasma levels, magnitude of biomarker (Ki67 LI, ER, and PgR) downregulation, and clinical activity were also assessed. Results: A total of 208 women were included in the PK analyses. Fulvestrant plasma levels and exposure were greater in the HD arm than the AD arm at Wks 4 and 16 (Wk 4: Cmax HD 24.5 ± 6.9 vs AD 8.8 ± 1.7 ng/mL; AUC0–28 days HD 12804 ± 3550 vs AD 4005 ± 840 ng.h/mL). Increased total monthly fulvestrant exposure correlated with increased downregulation of Ki67 LI, ER and PgR. Detailed modeling of the endpoints suggested a non-linear decrease in both Ki67 and PgR to a plateau of approximately 20–30% of the baseline values. ER levels were downregulated to approximately 50% of the pretreatment values. Conclusions: Increased fulvestrant exposure correlates with increased downregulation of Ki67 LI, ER and PgR. The relationship between drug levels and clinical response will be presented. Fulvestrant HD is currently being investigated in the metastatic disease setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca AstraZeneca
Maybe she's NOT the boss: male–female crosstalk during sexual plant reproduction
Authors: Hannes Vogler, Andrea Martinez-Bernardini, Ueli Grossniklaus
Journal: Genome biology (2016)

New insights into the molecular dialogue between male and female during sexual plant reproduction show that even plant sex does not work without clear communication. Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0928-x
Adjunctive therapy with intravenous human immunoglobulin G improves survival of patients with acute renal failure.
Authors: W F Keane, C A Hirata-Dulas, M L Bullock, A L Ney, D R Guay, R S Kalil, C A Dinarello, C E Halstenson, P K Peterson
Journal: Journal of the American Society of Nephrology (1991)

The objective of this prospective, randomized, double-blind, placebo-controlled clinical trial was to evaluate the efficacy of adjunctive therapy with iv human immunoglobulin G in reducing the morbidity and mortality associated with acute renal failure. Forty patients greater than or equal to 18 yr of age who were identified within 48 h of the onset of acute renal failure and who met the enrollment criteria were enrolled in the study. Thirty-five patients were considered evaluable. Patients were grouped according to the admitting service (medical or surgical/trauma) and were randomized to receive either immunoglobulin G (400 mg/kg body wt) or placebo (normal saline; 8 mL/kg body wt) at study entry and then weekly thereafter for a maximum of 4 doses. The groups were well balanced with respect to demographics, clinical presentation, and severity of illness (APACHE II scores). A significant reduction in mortality at 42 days after study entry was observed. Two of 17 (12%) patients in the immunoglobulin G-treated group compared with 8 of 18 (44%) patients in the placebo-treated group died (P = 0.025). No differences were observed in the frequency of major complications that occurred in association with acute renal failure. However, in patients who manifested infection, greater survival was observed in the immunoglobulin G treatment group. The results suggest that immunoglobulin G administered at the onset of acute renal failure reduced mortality possibly by decreasing the severity of infectious complications associated with the occurrence of of acute renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Lithium plus reserpine in refractory manic patients
Authors: N M Bacher, H A Lewis
Journal: American Journal of Psychiatry (1979)

The authors report on six refractory manic or schizo-affective manic male outpatients who failed to respond to lithium combined with a neuroleptic. A beneficial response was noted in most patients when reserpine was substituted for their currently prescribed standard neuroleptic; in some cases lithium dosage could then be reduced. No major side effects were encountered. The use of reserpine may offer an alternative mode of therapy for manic patients who cannot tolerate large doses of lithium or do not completely respond to lithium either alone or in combination with a standard neuroleptic.
Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses
Authors: Oliver Bannard, Simon J. McGowan, Jonatan Ersching, Satoshi Ishido, Gabriel D. Victora, Jeoung-Sook Shin, Jason G. Cyster
Journal: The Journal of Experimental Medicine (2016)

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and selection. Selection involves B cells competing for T cell help based on the amount of antigen they capture and present on their MHC class II (MHCII) proteins. How GC B cells are able to rapidly and repeatedly transition between mutating their B cell receptor genes and then being selected shortly after is not known. We report that MHCII surface levels and degradation are dynamically regulated in GC B cells. Through ectopic expression of a photoconvertible MHCII-mKikGR chimeric gene, we found that individual GC B cells differed in the rates of MHCII protein turnover. Fluctuations in surface MHCII levels were dependent on ubiquitination and the E3 ligase March1. Increases in March1 expression in centroblasts correlated with decreases in surface MHCII levels, whereas CD83 expression in centrocytes helped to stabilize MHCII at that stage. Defects in MHCII ubiquitination caused GC B cells to accumulate greater amounts of a specific peptide-MHCII (pMHCII), suggesting that MHCII turnover facilitates the replacement of old complexes. We propose that pMHCII complexes are periodically targeted for degradation in centroblasts to favor the presentation of recently acquired antigens, thereby promoting the fidelity and efficiency of selection.
Discussion of Case-Control Studies of Peleg, Stähelin, and Willett<xref ref-type="fn" rid="FN1">1</xref>
Authors: Daniel Seigel
 3
Journal: JNCI Journal of the National Cancer Institute (1984)

The combined results from the case-control studies of Peleg, Stähelin, and Willett were found to provide no evidence of a relationship between serum retinol levels and the risk of cancer in all sites combined or of lung cancer. However, a relationship between serum retinol levels and the risk of gastrointestinal cancer was suggested.
SAT0223 Actual Need in Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) in RA Patients Treated with Subcutaneous Methotrexate within “Treat to Target” Strategy
Authors: A. Karateev, D. Karateev, E. Luchikhina, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> NSAIDs are widely used in RA pts to control the main symptoms of the disease. However NSAIDs do not prevent RA progression and are associated with potential serious side effects. Therefore cutting down the use of NSAIDs leads to gastrointestinal (GI) and cardiovascular complications risk reduction, and should be considered as a criterion of efficacy. <h3>Objectives</h3> To evaluate the need in NSAIDs and rate of GI complications in RA patients managed according to "Treat to Target" strategy. <h3>Methods</h3> This study is a part of REMARCA program (abbreviation of Russian InvEstigation of MethotrexAte and biologics in eaRly aCtive inflammatory Arthritis). The study group included 141 RA patients (82.3% females and 17.7% males, mean age 50.3±12.8 y, disease duration 16,7±26,6 mo., including 51% of pts with disease duration of &lt;6 mo.). The majority of pts had high disease activity (DAS28 5.5±1.14, SDAI 30,3±14,5), were RF-positive (88%) and ACPA-positive (86%). 127 pts (90%) were regularly taking NSIADs, 26 (18.4%) - glucocorticoids. 10 pts (7.0%) had the history of gastric and/or duodenal ulcer, 32 (22.7%) – dyspepsia, 61 (43.2%) - H.pylori infection. 12 (8.5%) were regularly taking proton pump inhibitors (PPI). At the first stage of the study all pts were administered methotrexate injections (MTI), starting from 10 mg/week with further dose escalation up to 20-30 mg/week. To evaluate NSAIDs negative impact on upper GI tract all patients were subjected to upper GI tract endoscopy on enrollment and in 3 months after inclusion into the study. <h3>Results</h3> Considerable improvement was documented in all pts after 3 mo of MTI therapy: a decrease in DAS28 to 4.08±1.46 (p&lt;0,01), in SDAI - to 16.97±13.5 (p&lt;0,01). The number of pts regularly taking NSAIDs reduced from 90% to 48.2%. Baseline upper GI tract endoscopy revealed gastric and/or duodenal ulcers in 7 (4.9%) pts, multiple (&gt;10) gastric erosions - in 6 (4.3%) pts. Repeated endoscopic study in 3 mo after initiation of MTI did not find any ulcers, although multiple erosions were present in 3 (2.1%) pts. <h3>Conclusions</h3> Methotrexate injections allow to considerably cut down the need in NSAIDs within 3 mo after initiation of therapy. Discontinuation of NSAIDs in early RA pts is associated with significant reduction of GI complications risk. <h3>Disclosure of Interest</h3> None declared
Severe respiratory complex III defect prevents liver adaptation to prolonged fasting
Authors: Laura S. Kremer, Caroline L’hermitte-Stead, Pierre Lesimple, Mylène Gilleron, Sandrine Filaut, Claude Jardel, Tobias B. Haack, Tim M. Strom, Thomas Meitinger, Hatem Azzouz, Neji Tebib, Hélène Ogier de Baulny, Guy Touati, Holger Prokisch, Anne Lombès
Journal: Journal of Hepatology (2016)
Identification of selective cytotoxic and synthetic lethal drug responses in triple negative breast cancer cells
Authors: Prson Gautam, Leena Karhinen, Agnieszka Szwajda, Sawan Kumar Jha, Bhagwan Yadav, Tero Aittokallio, Krister Wennerberg
Journal: Molecular Cancer (2016)

Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive type of cancer that lacks effective targeted therapy. Despite detailed molecular profiling, no targeted therapy has been established. Hence, with the aim of gaining deeper understanding of the functional differences of TNBC subtypes and how that may relate to potential novel therapeutic strategies, we studied comprehensive anticancer-agent responses among a panel of TNBC cell lines.The responses of 301 approved and investigational oncology compounds were measured in 16 TNBC cell lines applying a functional profiling approach. To go beyond the standard drug viability effect profiling, which has been used in most chemosensitivity studies, we utilized a multiplexed readout for both cell viability and cytotoxicity, allowing us to differentiate between cytostatic and cytotoxic responses.Our approach revealed that most single-agent anti-cancer compounds that showed activity for the viability readout had no or little cytotoxic effects. Major compound classes that exhibited this type of response included anti-mitotics, mTOR, CDK, and metabolic inhibitors, as well as many agents selectively inhibiting oncogene-activated pathways. However, within the broad viability-acting classes of compounds, there were often subsets of cell lines that responded by cell death, suggesting that these cells are particularly vulnerable to the tested substance. In those cases we could identify differential levels of protein markers associated with cytotoxic responses. For example, PAI-1, MAPK phosphatase and Notch-3 levels associated with cytotoxic responses to mitotic and proteasome inhibitors, suggesting that these might serve as markers of response also in clinical settings. Furthermore, the cytotoxicity readout highlighted selective synergistic and synthetic lethal drug combinations that were missed by the cell viability readouts. For instance, the MEK inhibitor trametinib synergized with PARP inhibitors. Similarly, combination of two non-cytotoxic compounds, the rapamycin analog everolimus and an ATP-competitive mTOR inhibitor dactolisib, showed synthetic lethality in several mTOR-addicted cell lines.Taken together, by studying the combination of cytotoxic and cytostatic drug responses, we identified a deeper spectrum of cellular responses both to single agents and combinations that may be highly relevant for identifying precision medicine approaches in TNBC as well as in other types of cancers.
Exposures to Particulate Matter from the Eruptions of the Puyehue Volcano and Birth Outcomes in Montevideo, Uruguay
Authors: Ana Ines Balsa, Marcelo Caffera, Juanita Bloomfield
Journal: Environmental Health Perspectives (2016)

The ashes and dust resulting from the 2011 eruptions of the Puyehue volcano in Chile more than doubled monthly averages of PM10 concentrations in Montevideo, Uruguay. Few studies have taken advantage of natural experiments to assess the relationship between ambient air pollutant concentrations and birth outcomes.
High affinity promotes more effective ADCC by anti-HER2/neu monoclonal antibodies
Authors: Y. Tang, K. Alpaugh, J. Lou, S. Litwin, C. Shaller, G. Adams, J. Marks, L. Weiner
Journal: Journal of Clinical Oncology (2006)

2538 Background: Although monoclonal antibodies have emerged as useful cancer therapeutics, the antibody structural features and biologic properties that maximize therapeutic benefit are not fully understood. Antibody-dependent cellular cytotoxicity (ADCC) is believed to be a major mechanism of some anti-cancer antibodies. Herein, we describe the relationship between antibody affinity and the biologic properties of ADCC. Methods: A series of human IgG1 antibodies was created from the anti-HER2/neu C6.5 scFv and its affinity mutants (affinity ranging from 10 −7 to 10 −11 M). The IgGs were tested for their ability to elicit ADCC using a standard 51 Cr-release assay. The ability of these IgGs to inhibit tumor cell proliferation and to induce apoptosis was evaluated using a colorimetric cell proliferation assay and homogeneous caspase assay/Annexin-V-FLUOS assay, respectively. Three tumor cell lines with differing levels of HER2/neu expression were used as target cells, and unactivated human PBMC from healthy donors were the effector cells. Results: There was a clear influence of both intrinsic and functional affinity on ADCC, with higher levels of peak cytotoxicity as apparent affinity approached 10 −11 M. Among the antibodies with apparent affinity of 10 −11 M, antibodies with higher intrinsic affinities elicited more ADCC. There also was an affinity-dependent increase in cytotoxicity at lower antibody concentrations and lower effector: target ratios. These antibodies elicited more cytotoxicity against tumor cells expressing high levels of HER2/neu than against cells expressing lower amounts of HER2/neu. None of these IgGs inhibited tumor cell proliferation, or induced apoptosis. Conclusions: Additional studies are needed to determine why, at the same functional avidity, ADCC is improved in antibodies with higher intrinsic affinities. These findings justify the examination of high affinity antibodies for ADCC promotion, although the impaired tumor targeting associated with high affinity may be an important confounding factor in the design of unconjugated anti-tumor antibodies. A careful examination of antibody structure: function relationships is required to develop optimized therapeutic unconjugated antibodies. No significant financial relationships to disclose.