tbuckley/cabot-search huggingface dataset:
A phase I study of the toll-like receptor 5 (TLR5) agonist, entolimod in patients (pts) with advanced cancers.
Authors: Hatoon Bakhribah, Grace K. Dy, Wen Wee Ma, Yujie Zhao, Mateusz Opyrchal, Andrei Purmal, Sandra Gollnick, William E. Brady, Gerald J. Fetterly, Nuttapong Ngamphaiboon, Thanyanan Reungwetwattana, Sandra M Jacob, Corrie O'Hara, Francine Siedlecki, Araba Adjei, Lyudmila Burdelya, Ivan Bespalov, Langdon L. Miller, Andrei Gudkov, Alex A. Adjei
Journal: Journal of Clinical Oncology (2015)

3063 Background: Entolimod is a specific, TLR5 agonist derived from salmonella flagellin, with immunotherapeutic effects in preclinical cancer models. Entolimod activates innate and adaptive immune responses and mobilizes immunocytes to organs such as liver and bladder, with functional TLR5. A phase 1 trial was undertaken to evaluate entolimod's safety, tolerability, pharmacokinetics, immunoactivity, and preliminary antitumor activity. Methods: Pts with advanced cancers and ECOG PS of 0-1 were treated at 5 subcutaneous doses (5, 10, 15, 20, 30, 40 µg/day) over a 2-week period. PK/PD samples were obtained pre, and 2, 4, 6, 8, 24 hrs post-dose. Immune function samples were obtained pre and 24 hrs post-dose on days1, 8, 11 and 22. Results: 26 pts (38.4% colorectal cancer [CRC] and 19% NSCLC) were enrolled. Common toxicities were transient hypotension (9 grade 1/4, 7 grade 2/4), hyperglycemia (8 grade 1/4, 6 grade 2/4), and fever (10 grade 1/4, 3 grade 2/4). Three DLTs were observed at 40 µg/day. One pt developed grade 3 rigors and pyrexia, a 2nd pt had grade 3 transaminitis; a 3rd had grade 3 hypotension. Tmax was 2 to 6 hrs and t1/2 was 3 to 7 hrs with little change between 1st and subsequent doses. Pharmacogenetic analysis revealed that 6 SNPs in the TLR5 gene were associated with LFT elevations (p < 0.05) Induced plasma cytokines included G-CSF, IL-6, IL-8 and IL-10 with no indications of cytokine storm. Pts exhibited immune cell activation with a stable or decrease in the levels of suppressive immune cells, accompanied by increased immunostimulatory and decreased immunosuppressive cytokines. Stable disease (SD) for > 6 weeks was observed in 8 pts, with 3 pts (anal, CRC and urothelial cancer) maintaining SD for > 12 weeks. Neutralizing antibodies developed by the 2nd week in most pts, indicating immune memory for flagellin. Conclusions: The recommended phase II dose of entolimod was30 µg/day on days 1, 4, 8, 11. The clinical results corroborated pre-clinical findings and support entolimod's potential as an immunotherapeutic agent. The safety profile suggests that entolimod can be combined with chemotherapeutic, targeted, or other immunotherapeutic agents. Clinical trial information: NCT01527236.
The Dendritic Cell System and its Role in Immunogenicity
Authors: R M Steinman
Journal: Annual Review of Immunology (1991)

Dendritic cells are a system of antigen presenting cells that function to initiate several immune responses such as the sensitization of MHC-restricted T cells, the rejection of organ transplants, and the formation of T-dependent antibodies. Dendritic cells are found in many nonlymphoid tissues but can migrate via the afferent lymph or the blood stream to the T-dependent areas of lymphoid organs. In skin, the immunostimulatory function of dendritic cells is enhanced by cytokines, especially GM-CSF. After foreign proteins are administered in situ, dendritic cells are a principal reservoir of immunogen. In vitro studies indicate that dendritic cells only process proteins for a short period of time, when the rate of synthesis of MHC products and content of acidic endocytic vesicles are high. Antigen processing is selectively dampened after a day in culture, but the capacity to stimulate responses to surface bound peptides and mitogens remains strong. Dendritic cells are motile, and efficiently cluster and activate T cells that are specific for stimuli on the cell surface. High levels of MHC class-I and -II products and several adhesins, such as ICAM-1 and LFA-3, likely contribute to these functions. Therefore dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells. The function of these presenting cells in immunologic tolerance is just beginning to be studied.
The Importance of Quality of Life Assessment
Authors: Charles R. Thomas
Journal: JAMA Oncology (2015)

Benjamin Movsas, MD; Chen Hu, PhD; Jeffrey Sloan, PhD, HSR; Jeffrey Bradley, MD; Ritsuko Komaki, MD; Gregory Masters, MD; Vivek Kavadi, MD; Samir Narayan, MD; Jeff Michalski, MD; Douglas W. Johnson, MD; Christopher Koprowski, MD; Walter J. Curran Jr, MD; Yolanda I. Garces, MD; Rakesh Gaur, MD; Raymond B. Wynn, MD; John Schallenkamp, MD; Daphna Y. Gelblum, MD; Robert M. MacRae, MD; Rebecca Paulus, BS; Hak Choy, MD
Characterization of the Causative Allergens for Wheat-Dependent Exercise-Induced Anaphylaxis Sensitized with Hydrolyzed Wheat Proteins in Facial Soap
Authors: Tomoharu Yokooji, Saki Kurihara, Tomoko Murakami, Yuko Chinuki, Susumu Harada, Hitoshi Takahashi, Eishin Morita, Kaori Ishii, Makiko Hiragun, Michihiro Hide, Hiroaki Matsuo
Journal: Journal of Allergy and Clinical Immunology (2013)
Arts and Brain-Computer Interfaces (BCIs)
Authors: Anton Nijholt, Chang S. Nam
Journal: Brain-Computer Interfaces (2015)

The primary goal of this special issue is to address contemporary challenges involved in designing BCI applications related to the creation and experience of art. This involves a low level artistic audification and visualization of brain activity patterns, a higher level musification and animation, and the control of instruments and tools. From 14 submissions initially received, eight articles were selected for publication after a rigorous two-step review process supported by experts in the areas of brain-computer interface, human-computer interaction, and human factors/ergonomics. The papers in the special issue present empirical and survey studies that explore contemporary research challenges involved in designing, developing and evaluating BCI applications related to the creation and experience of art.
Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer.
Authors: G R Hudes, R Greenberg, R L Krigel, S Fox, R Scher, S Litwin, P Watts, L Speicher, K Tew, R Comis
Journal: Journal of Clinical Oncology (1992)

PURPOSE Estramustine phosphate (EMP) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro. Their modest single-agent activities in hormone-refractory prostate cancer, nonoverlapping toxicities, and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer. PATIENTS AND METHODS Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously (IV) once a week for 6 weeks. Courses were repeated every 8 weeks. Response assessment was based on a change in serum prostate-specific antigen (PSA) levels and was correlated with change in pain scores. RESULTS PSA decreased from baseline by at least 50% in 22 patients (61.1%) and by &gt; or = 75% in eight patients (22.2%). A 50% or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score, performance status, and measurable soft tissue disease (if present) was required for a partial response (PR), which occurred in 11 patients for an overall response rate of 30.5% (95% confidence interval, 15.6% to 45.6%). In seven patients with measurable nonosseous disease, there was one PR (14%) and one minor response (MR). In 28 patients with assessable pain, major pain responses occurred in 12 (42.9%). PSA response (&gt; or = 50% decrease times three measurements) was predictive of major pain response with a 93.7% specificity, a 50% sensitivity, and a positive predictive value of 85.7%. CONCLUSION We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer.
Long-Term Clinical Impact of Coronary CT Angiography in Patients With Recent Acute-Onset Chest Pain
Authors: Jesper J. Linde, Jens D. Hove, Mathias Sørgaard, Henning Kelbæk, Gorm B. Jensen, Jørgen T. Kühl, Louise Hindsø, Lars Køber, Walter B. Nielsen, Klaus F. Kofoed
Journal: JACC. Cardiovascular imaging (2015)
Identification of low abundance microbiome in clinical samples using whole genome sequencing
Authors: Chao Zhang, Kyle Cleveland, Felice Schnoll-Sussman, Bridget McClure, Michelle Bigg, Prashant Thakkar, Nikolaus Schultz, Manish A. Shah, Doron Betel
Journal: Genome biology (2015)

Identifying the microbiome composition from primary tissues directly affords an opportunity to study the causative relationships between the host microbiome and disease. However, this is challenging due the low abundance of microbial DNA relative to the host. We present a systematic evaluation of microbiome profiling directly from endoscopic biopsies by whole genome sequencing. We compared our methods with other approaches on datasets with previously identified microbial composition. We applied this approach to identify the microbiome from 27 stomach biopsies, and validated the presence of Helicobacter pylori by quantitative PCR. Finally, we profiled the microbial composition in The Cancer Genome Atlas gastric adenocarcinoma cohort.
Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two-stage trial design for patients with advanced malignancy.
Authors: J Berlin, J A Stewart, B Storer, K D Tutsch, R Z Arzoomanian, D Alberti, C Feierabend, K Simon, G Wilding
Journal: Journal of Clinical Oncology (1998)

PURPOSE A novel phase I trial design was used to determine the maximum-tolerated dose (MTD) and pharmacokinetics for penclomedine when administered as an intravenous (i.v.) infusion over 1 hour daily for 5 days, repeated every 28 days. This study also tests the feasibility of a novel two-stage design for phase I trials. PATIENTS AND METHODS Twenty-eight patients with advanced malignancy who met standard eligibility criteria were treated with i.v. penclomedine. The initial daily dose was 50 mg/m2. Dose escalations were planned using a modified Fibonacci sequence. One patient was enrolled on each dose level during the first stage of this trial. In the second stage, patients were enrolled in cohorts of three, proceeding in an up-and-down manner based on toxicities observed. MTD was determined by logistic regression analysis. Pharmacokinetic assessment was performed during the first cycle of treatment. RESULTS Dose-limiting toxicities (DLT) observed during this trial were principally neurologic and were self-limited. Although hematologic toxicity was rare, the few patients with significant hematologic changes experienced late nadirs with prolonged time to recovery. The MTD was estimated as 381 mg/m2 (80% CI, 343 to 415 mg/m2). Although there was a long elimination half-life, accumulation of penclomedine over the 5 days of administration was negligible. CONCLUSION The novel trial design used in this study was safe and appeared effective in limiting the numbers of patients treated at lower-dose levels. Reversible neurotoxicity was dose-limiting. Although the estimated MTD was 381 mg/m2, any dose within the CI would be reasonable for phase II study.
No added value of interferon-γ release to a prediction model for childhood tuberculosis
Authors: Toyin O. Togun, Uzochukwu Egere, Marie P. Gomez, Abdou K. Sillah, Mohammed Daramy, Leopold D. Tientcheu, Jayne S. Sutherland, Philip C. Hill, Beate Kampmann
Journal: European Respiratory Journal (2015)

The predictive value of a combination of clinical and radiological features with interferon-γ release assay (IGRA) for diagnosis of active tuberculosis (TB) disease among TB-exposed children is unknown.150 symptomatic HIV-negative children (aged 3 months to 14 years), prospectively recruited through active contact tracing, were included. Backward stepwise logistic regression and bootstrapping techniques were used for the development and internal validation of a clinical prediction model for active TB disease. Model discrimination and incremental value of a positive IGRA test were assessed by area under the receiver operating characteristic curve (AUC).35 (23%) children were diagnosed with active TB disease and started on treatment and 115 (77%) had other respiratory tract infections. A final parsimonious clinical model, comprising age <5 years (adjusted (a)OR 4.8, 95% CI 2.0-11.5) and lymphadenopathy on clinical examination (aOR 4.9, 95% CI 1.8-13.0) discriminated active TB disease from other disease with an AUC of 0.70 (95% CI 0.61-0.80). A positive IGRA result did not improve the discriminatory ability of the clinical model (c-statistic 0.72 versus 0.70; p=0.644).A clinical algorithm, including age <5 years and lymphadenopathy classified 70% of active TB disease among symptomatic TB-exposed children. IGRA does not add any discriminatory value to this prediction model.
In Vivo Efficacy of PI3K Pathway Signaling Inhibition for Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia
Authors: Sarah K. Tasian, Yong Li, Theresa Ryan, Tiffaney Vincent, David T. Teachey, Mignon L. Loh, Stephen P. Hunger, Martin Carroll, Stephan A. Grupp
Journal: Blood (2013)
Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications
Authors: Malcolm Collins, Alison V September, Michael Posthumus
Journal: British Journal of Sports Medicine (2015)

Evidence from familial and genetic association studies have reported that DNA sequence variants play an important role, together with non-genetic factors, in the aetiology of both exercise-associated and occupational-associated acute and chronic musculoskeletal soft tissue injuries. The associated variants, which have been identified to date, may contribute to the interindividual variation in the structure and, by implication, mechanical properties of the collagen fibril and surrounding matrix within musculoskeletal soft tissues, as well as their response to mechanical loading and other stimuli. Future work should focus on the establishment of multidisciplinary international consortia for the identification of biologically relevant variants involved in modulating injury risk. These consortia will improve the limitations of the published hypothesis-driven genetic association studies, since they will allow resources to be pooled in recruiting large well-characterised cohorts required for whole-genome screening. Finally, clinicians and coaches need to be aware that many direct-to-consumer companies are currently marketing genetic tests directly to athletes without it being requested by an appropriately qualified healthcare professional, and without interpretation alongside other clinical indicators or lifestyle factors. These specific genetic tests are premature and are not necessarily required to evaluate susceptibility to musculoskeletal soft tissue injury. Current practice should rather consider susceptibility through known risk factors such as a positive family history of a specific injury, a history of other tendon and/or ligament injuries and participation in activities associated with the specific musculoskeletal injuries. Potential susceptible athletes may then be individually managed to reduce their risk profile.
Patterns of Chemotherapy Administration in High-Risk Soft Tissue Sarcoma and Impact on Overall Survival
Authors: Sujana Movva, Margaret von Mehren, Eric A. Ross, Elizabeth Handorf
Journal: Journal of the National Comprehensive Cancer Network (2015)

Conflicting data exist on the benefit of chemotherapy in the management of high-risk soft tissue sarcoma (STS). Use of chemotherapy may be dependent on patient, tumor, and facility characteristics. This study sought to identify these factors and compare survival between treatment groups.Patients with stage III STS were identified from the National Cancer Data Base (NCDB) from 1998 to 2012. Multiple logistic regression analysis was used to determine factors that influenced the probability of receiving chemotherapy. In a subset of patients, we determined the relationship between chemotherapy use and overall survival, using Kaplan-Meier curves and Cox regression analysis with propensity score adjustment. We also examined the effect of chemotherapy by histologic subgroup using interaction models.A total of 16,370 patients were included (N=5,377 for survival analysis). Patients who were younger than 40 years; male; privately insured; earned a higher income; had no comorbidities; had synovial sarcoma, angiosarcoma or "other" histology; and whose tumors were high-grade, greater than 10 cm, or from the lower extremity were significantly more likely to receive chemotherapy. Median unadjusted overall survival (OS) in the nonchemotherapy and chemotherapy groups was 51.3 and 82.7 months, respectively (P<.001). On adjusted analysis, the survival benefit remained significant (hazard ratio [HR], 0.85; P=.004). The benefit was particularly strong in the undifferentiated pleomorphic sarcoma (UPS) group on adjustment, with a median OS of 49.1 and 77.8 months for nonchemotherapy versus chemotherapy, respectively (HR, 0.77; P=.02).In addition to expected tumor and patient factors, histology, location of primary tumor, and socioeconomic status are associated with receipt/nonreceipt of chemotherapy in stage III STS. Chemotherapy use was associated with improved OS in the overall population, and specifically in the UPS subgroup.
Abstract 5198: Contribution of inflammatory cytokines to CD44-mediated breast cancer metastatic potential
Authors: Hunter Covert, Liliana Mellor
Journal: Cancer Research (2015)

Abstract The purpose of this study was to elucidate the relationship between the inflammatory cytokine oncostatin M (OSM) and cell migration-promoting CD44 in breast cancer metastasis. OSM-induced CD44 expression was studied in multiple human breast cancer cell lines, including triple negative (TNBC) MDA-MB-231 and estrogen receptor/progesterone receptor-positive (ER+/PR+) T47D and MCF-7 cells. Western blot analysis and RT-PCR demonstrated that OSM is capable of upregulating the expression of the standard form of CD44 (CD44s), as well as inducing multiple CD44 variants produced by alternative splicing. Confocal microscopy was performed and displayed highly organized CD44 around the edge of the cell after OSM treatment. OSM treatment also increased the breast cancer stem cell (BCSC) population (CD44+/CD24−), as measured by flow cytometry. To examine the importance of OSM-induced CD44 in tumor cell migration, we conducted migration assays with and without siCD44 and treatment with OSM. These results verified that OSM-induced CD44 is important for cellular migration. In conclusion, our studies demonstrate that OSM increases the expression of CD44s and its variants, as well as induce a BCSC phenotype. Furthermore, we show that OSM-induced CD44 plays a role in migration, which is an essential characteristic of breast cancer metastasis. Citation Format: Hunter Covert, Liliana Mellor. Contribution of inflammatory cytokines to CD44-mediated breast cancer metastatic potential. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5198. doi:10.1158/1538-7445.AM2015-5198
Identification of a novel cis-regulatory element essential for immune tolerance
Authors: Taylor N. LaFlam, Grégory Seumois, Corey N. Miller, Wint Lwin, Kayla J. Fasano, Michael Waterfield, Irina Proekt, Pandurangan Vijayanand, Mark S. Anderson
Journal: The Journal of Experimental Medicine (2015)

Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.
Dense Deposit Disease Mimicking a Renal Small Vessel Vasculitis
Authors: Lavleen Singh, Geetika Singh, Swati Bhardwaj, Aditi Sinha, Arvind Bagga, Amit Dinda
Journal: Journal of the American Society of Nephrology (2015)

Dense deposit disease is caused by fluid-phase dysregulation of the alternative complement pathway and frequently deviates from the classic membranoproliferative pattern of injury on light microscopy. Other patterns of injury described for dense deposit disease include mesangioproliferative, acute proliferative/exudative, and crescentic GN. Regardless of the histologic pattern, C3 glomerulopathy, which includes dense deposit disease and C3 GN, is defined by immunofluorescence intensity of C3c two or more orders of magnitude greater than any other immune reactant (on a 0-3 scale). Ultrastructural appearances distinguish dense deposit disease and C3 GN. Focal and segmental necrotizing glomerular lesions with crescents, mimicking a small vessel vasculitis such as ANCA-associated GN, are a very rare manifestation of dense deposit disease. We describe our experience with this unusual histologic presentation and distinct clinical course of dense deposit disease, discuss the pitfalls in diagnosis, examine differential diagnoses, and review the relevant literature.
Aldosterone, the Adrenal Cortex, and Hypertension
Authors: E N Ehrlich
Journal: Annual Review of Medicine (1968)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
Transsphenoidal Surgery for Cushing's Disease
Authors: R Fahlbusch, M Buchfelder, O A Müller
Journal: Journal of the Royal Society of Medicine (1986)

A series of 101 patients with Cushing's disease underwent transsphenoidal surgery. Diagnosis was fundamentally based on dynamic testing, mainly on the dosage-dependent suppression of cortisol after dexamethasone. The effect of surgery was monitored by intraoperative ACTH measurements. In 96 out of 101 patients a microadenoma of the pituitary was identified and removed selectively. In 74% of patients there was a clinical and endocrinological remission of Cushing's disease. Four ‘operative failures’ after selective adenomectomy underwent hypophysectomy in a second operation and each remitted. Thus the overall remission rate was 77%. In general, bilateral adrenalectomy was performed in patients who had failed to remit after selective adenomectomy. Although there is a considerable mortality and morbidity in patients with Cushing's syndrome, complications attributed to surgery were low. Two patients died postoperatively. In general, an improvement of disturbed pituitary function was noted after selective adenomectomy.
Carcinogenicity of TCDD: Experimental, Mechanistic, and Epidemiologic Evidence
Authors: J Huff, G Lucier, A Tritscher
Journal: The Annual Review of Pharmacology and Toxicology (1994)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More