tbuckley/cabot-search huggingface dataset:
Sequential Duplications of an Ancient Member of the DnaJ-Family Expanded the Functional Chaperone Network in the Eukaryotic Cytosol
Authors: Chandan Sahi, Jacek Kominek, Thomas Ziegelhoffer, Hyun Young Yu, Maciej Baranowski, Jaroslaw Marszalek, Elizabeth A. Craig
Journal: Molecular Biology and Evolution (2013)

Across eukaryotes, Hsp70-based chaperone machineries display an underlying unity in their sequence, structure, and biochemical mechanism of action, while working in a myriad of cellular processes. In good part, this extraordinary functional versatility is derived from the ability of a single Hsp70 to interact with an array of J-protein cochaperones to form a functional chaperone network. Among J-proteins, the DnaJ-type is the most prevalent, being present in all three kingdoms and in several different compartments of eukaryotic cells. However, because these ancient DnaJ-type proteins diverged at the base of the eukaryotic phylogeny, little is understood about the evolutionary basis of their diversification and thus the functional expansion of the chaperone network. Here, we report results of evolutionary and experimental analyses of two more recent members of the cytosolic DnaJ family of Saccharomyces cerevisiae, Xdj1 and Apj1, which emerged by sequential duplications of the ancient YDJ1 in Ascomycota. Sequence comparison and molecular modeling revealed that both Xdj1 and Apj1 maintained a domain organization similar to that of multifunctional Ydj1. However, despite these similarities, both Xdj1 and Apj1 evolved highly specialized functions. Xdj1 plays a unique role in the translocation of proteins from the cytosol into mitochondria. Apj1’s specialized role is related to degradation of sumolyated proteins. Together these data provide the first clear example of cochaperone duplicates that evolved specialized functions, allowing expansion of the chaperone functional network, while maintaining the overall structural organization of their parental gene.
Targeting Human γδ T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer
Authors: Francesco Dieli, David Vermijlen, Fabio Fulfaro, Nadia Caccamo, Serena Meraviglia, Giuseppe Cicero, Andrew Roberts, Simona Buccheri, Matilde D'Asaro, Nicola Gebbia, Alfredo Salerno, Matthias Eberl, Adrian C. Hayday
Journal: Cancer Research (2007)

Abstract The increasing evidence that γδ T cells have potent antitumor activity suggests their value in immunotherapy, particularly in areas of unmet need such as metastatic carcinoma. To this end, we initiated a phase I clinical trial in metastatic hormone-refractory prostate cancer to examine the feasibility and consequences of using the γδ T-cell agonist zoledronate, either alone or in combination with low-dose interleukin 2 (IL-2), to activate peripheral blood γδ cells. Nine patients were enlisted to each arm. Neither treatment showed appreciable toxicity. Most patients were treated with zoledronate + IL-2, but conversely only two treated with zoledronate displayed a significant long-term shift of peripheral γδ cells toward an activated effector-memory–like state (TEM), producing IFN-γ and perforin. These patients also maintained serum levels of tumor necrosis factor–related apoptosis inducing ligand (TRAIL), consistent with a parallel microarray analysis showing that TRAIL is produced by γδ cells activated via the T-cell receptor and IL-2. Moreover, the numbers of TEM γδ cells showed a statistically significant correlation with declining prostate-specific antigen levels and objective clinical outcomes that comprised three instances of partial remission and five of stable disease. By contrast, most patients treated only with zoledronate failed to sustain either γδ cell numbers or serum TRAIL, and showed progressive clinical deterioration. Thus, zoledronate + IL-2 represents a novel, safe, and feasible approach to induce immunologic and clinical responses in patients with metastatic carcinomas, potentially providing a substantially increased window for specific approaches to be administered. Moreover, γδ cell phenotypes and possibly serum TRAIL may constitute novel biomarkers of prognosis upon therapy with zoledronate + IL-2 in metastatic carcinoma. [Cancer Res 2007;67(15):7450–7]
PROPERTIES OF THE TYPE SPECIFIC PROTEINS OF ANTIPNEUMOCOCCUS SERA
Authors: Kenneth Goodner, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1937)

The ability to carry out with some measure of precision mouse protection tests for the estimation of potency of antipneumococcus sera has made possible the correlation of the protective potency with the amount of specifically precipitable protein. With antipneumococcus rabbit sera these protective ratios are relatively constant and higher than those with immune horse serum. Type I antipneumococcus horse sera, on the other hand, show no such constancy but fall into two groups; and there is as yet no simple method for determining to which group a serum belongs.
Mln0264, an Investigational, First-In-Class Antibody-Drug Conjugate Targeting Guanylyl Cyclase C (Gcc): First-In-Human Study in Patients with Advanced Gastrointestinal Malignancies
Authors: Wells Messersmith, Khaldoun Almhanna, Jordi Rodon, Cristina Cruz, David Ryan, JungAh Jung, Adedigbo Fasanmade, Tim Wyant, Thea Kalebic
Journal: Annals of Oncology (2013)
Neoadjuvant Therapy for Breast Cancer
Authors: Dimitrios Zardavas, Martine Piccart
Journal: Annual Review of Medicine (2014)

Neoadjuvant treatment of breast cancer refers to the use of different treatment modalities prior to surgical excision of the tumor. It has been accepted as a treatment option for patients with nonmetastatic disease, because it renders inoperable tumors operable and increases the rates of breast-conserving surgery, while achieving similar long-term clinical outcomes as adjuvant treatment. The neoadjuvant setting is being increasingly perceived as a research platform, where the biologic effects of traditional anticancer agents can be delineated, prognostic and predictive biomarkers can be identified, and the development of targeted agents can be expedited. Surrogate endpoints that can predict long-term clinical outcome and are evaluable early on, such as the pathologic complete response, offer valuable opportunities for rapid assessment of anticancer agents. Additionally, efforts for molecular profiling of the post-neoadjuvant residual disease hold the potential to lead to personalized therapy for breast cancer patients with early-stage high-risk disease.
Four-Week Prevalence of Mental Disorders in Patients With Cancer Across Major Tumor Entities
Authors: Anja Mehnert, Elmar Brähler, Hermann Faller, Martin Härter, Monika Keller, Holger Schulz, Karl Wegscheider, Joachim Weis, Anna Boehncke, Bianca Hund, Katrin Reuter, Matthias Richard, Susanne Sehner, Sabine Sommerfeldt, Carina Szalai, Hans-Ulrich Wittchen, Uwe Koch
Journal: Journal of Clinical Oncology (2014)

Purpose To provide the 4-week prevalence estimates of mental disorders in cancer populations. Patients and Methods We enrolled adult patients with cancer from in- and outpatient care facilities, using a proportional stratified random sample based on the nationwide cancer incidence in Germany. Patients who scored 9 or above on the Patient Health Questionnaire (PHQ-9) were administered to the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). A random sample of those with a PHQ-9 score that was less than 9 were selected for a CIDI-O. Results A total of 5,889 patients were identified, which led to 4,020 participants (a 68.3% response rate); of those, 2,141 patients were interviewed. The 4-week total prevalence for any mental disorder was 31.8% (95% CI, 29.8% to 33.8%); this included any anxiety disorder (11.5%; 95% CI, 10.2% to 12.9%), any adjustment disorder (11.1%; 95% CI, 9.7% to 12.4%), any mood disorder (6.5%; 95% CI, 5.5% to 7.5%), any somatoform/conversion disorder (5.3%; 95% CI, 4.3% to 6.2%), nicotine dependence (4.5%; 95% CI, 3.6% to 5.4%), alcohol abuse/dependence (0.3%; 95% CI, 0.1% to 0.6%), any mental disorder resulting from general medical condition (2.3%; 95% CI, 1.7% to 2.9%), and any eating disorder (0%). The highest prevalence for any mental disorder was found in patients with breast cancer (41.6%; 95% CI, 36.8% to 46.4%), followed by patients with head and neck cancer (40.8%; 95% CI, 28.5% to 53.0%). The lowest prevalence was found in patients with pancreatic cancer (20.3%; 95% CI, 8.9% to 31.6%) and stomach/esophagus cancers (21.2%; 95% CI, 12.8% to 29.6%). Conclusion Our findings provide evidence for the strong need for psycho-oncological interventions.
Immunoglobulin E plus antigen challenge induces a novel intercrine/chemokine in mouse mast cells.
Authors: P A Kulmburg, N E Huber, B J Scheer, M Wrann, T Baumruker
Journal: The Journal of Experimental Medicine (1992)

In an attempt to characterize genes participating in the allergic late phase reaction, we have isolated a novel intercrine/chemokine (called MARC) from a cDNA library of the stimulated mouse mast cell line, CPII. As measured by Northern blotting, it is strongly upregulated at the mRNA level after the physiological challenge of the cells with immunoglobulin (Ig)E plus antigen. Unstimulated cells completely lack significant, stable expression, as do a number of other, different cell lines (uninduced and induced) and mouse tissues. In contrast to the Northern blot analysis, a polymerase chain reaction (PCR) analysis, performed on CPII cells and on Percoll gradient purified mouse peritoneal mast cells, revealed a basal level of transcription in the uninduced stage. After 2 h of IgE plus antigen challenge, a quantitative reverse transcriptase-PCR, using a spiked in MIMIC, showed a level of transcripts more than 100-fold higher in the CPII cells and 5-20-fold higher in purified mouse peritoneal cavity mast cells. This rapid induction after the Fc epsilon RI challenge, the identification of the gene as a member of the chemokine family, and its upregulated expression in peritoneal mast cells, all suggest an involvement in certain acute and chronic pathological mast cell-driven diseases.
Preliminary Report on Experiments upon Intestinal Absorption without Osmosis
Authors: E. W. Reid
Journal: BMJ (1892)

INTESTINAL ABSORPTION WITHOUT OSMOSIS..[CJOUNA 1133 fectant properties of iodoform.First, it was ascertaintd that iodoform was not infective.Dusted on the surface of broth, it floated for days at a temperature of 230 C., but soon mingled with the broth at 370 0. Tubes which had been treated in this way were good culture media for staphylococcus aureus.Next, plate cultures of gelatine and of agar-agar were infected, some with straphylococcus aureus, others with skin microbes, such as staphylococcus albus, diplococcus albus, and diplococcus citreus.Broth cultures inoculated from
Bone mineral density in patients with hand osteoarthritis compared to population controls and patients with rheumatoid arthritis
Authors: I K Haugen, B Slatkowsky-Christensen, R Orstavik, T K Kvien
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Several studies have revealed increased bone mineral density (BMD) in patients with knee or hip osteoarthritis, but few studies have addressed this issue in hand osteoarthritis (HOA). The aims of this study were to compare BMD levels and frequency of osteoporosis between female patients with HOA, rheumatoid arthritis (RA) and controls aged 50–70 years, and to explore possible relationships between BMD and disease characteristics in patients with HOA. <h3>Methods:</h3> 190 HOA and 194 RA patients were recruited from the respective disease registers in Oslo, and 122 controls were selected from the population register of Oslo. All participants underwent BMD measurements of femoral neck, total hip and lumbar spine (dual-energy <i>x</i> ray absorptiometry), interview, clinical joint examination and completed self-reported questionnaires. <h3>Results:</h3> Age-, weight- and height-adjusted BMD values were significantly higher in HOA versus RA and controls, the latter only significant for femoral neck and lumbar spine. The frequency of osteoporosis was not significantly different between HOA and controls, but significantly lower in HOA versus RA. Adjusted BMD values did not differ between HOA patients with and without knee OA, and significant associations between BMD levels and symptom duration or disease measures were not observed. <h3>Conclusion:</h3> HOA patients have a higher BMD than population-based controls, and this seems not to be limited to patients with involvement of larger joints. The lack of correlation between BMD and disease duration or severity does not support the hypothesis that higher BMD is a consequence of the disease itself.
Regulation of peripheral T cell activation by calreticulin
Authors: Simona Porcellini, Elisabetta Traggiai, Ursula Schenk, Denise Ferrera, Michela Matteoli, Antonio Lanzavecchia, Marek Michalak, Fabio Grassi
Journal: The Journal of Experimental Medicine (2006)

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt−/− hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt−/− T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.
Nuclear translocation of urokinase-type plasminogen activator
Authors: Victoria Stepanova, Tatiana Lebedeva, Alice Kuo, Serge Yarovoi, Sergei Tkachuk, Sergei Zaitsev, Khalil Bdeir, Inna Dumler, Michael S. Marks, Yelena Parfyonova, Vsevolod A. Tkachuk, Abd Al-Roof Higazi, Douglas B. Cines
Journal: Blood (2008)
Gas, dust, and fumes exposure is associated with mite sensitization and with asthma in mite‐sensitized adults
Authors: A. Bjerg, E.P. Rönmark, S. Hagstad, J. Eriksson, M. Andersson, G. Wennergren, K. Torén, L. Ekerljung
Journal: Allergy (2015)

Occupational exposure to gas, dust, and fumes (GDF) increases the risk of asthma and eczema. We investigated the role of sensitization in the association between GDF and allergic conditions. A population-based sample of 788 adults from the West Sweden Asthma Study completed questionnaires and skin prick tests. After adjustment for confounders, GDF exposure was associated with a doubled risk of sensitization to mites, but not with other allergens. Mite sensitization also modified the effect of GDF on asthma. In mite-sensitized subjects, GDF was associated with physician-diagnosed asthma, adjusted OR 2.9 (1.2-7.2), and with wheeze, OR 2.4 (1.1-5.3). In non-mite-sensitized subjects, the corresponding ORs were 1.1 (0.5-2.6) and 0.6 (0.3-1.3). GDF was independently associated with eczema regardless of mite sensitization, but not with rhinitis. These novel findings suggest that components of GDF may act as adjuvants that facilitate sensitization to mites and that mite-sensitized individuals may be especially susceptible to inhalant occupational exposures.
Inhibition of Multidrug-resistant Acinetobacter baumannii by Nonviral Expression of hCAP-18 in a Bioengineered Human Skin Tissue
Authors: Christina L Thomas-Virnig, John M Centanni, Colette E Johnston, Li-Ke He, Sandy J Schlosser, Kelly F Van Winkle, Ruibing Chen, Angela L Gibson, Andrea Szilagyi, Lingjun Li, Ravi Shankar, B Lynn Allen-Hoffmann
Journal: Molecular Therapy (2009)

When skin is compromised, a cascade of signals initiates the rapid repair of the epidermis to prevent fluid loss and provide defense against invading microbes. During this response, keratinocytes produce host defense peptides (HDPs) that have antimicrobial activity against a diverse set of pathogens. Using nonviral vectors we have genetically modified the novel, nontumorigenic, pathogen-free human keratinocyte progenitor cell line (NIKS) to express the human cathelicidin HDP in a tissue-specific manner. NIKS skin tissue that expresses elevated levels of cathelicidin possesses key histological features of normal epidermis and displays enhanced antimicrobial activity against bacteria in vitro. Moreover, in an in vivo infected burn wound model, this tissue results in a two log reduction in a clinical isolate of multidrug-resistant Acinetobacter baumannii. Taken together, these results suggest that this genetically engineered human tissue could be applied to burns and ulcers to counteract bacterial contamination and prevent infection. When skin is compromised, a cascade of signals initiates the rapid repair of the epidermis to prevent fluid loss and provide defense against invading microbes. During this response, keratinocytes produce host defense peptides (HDPs) that have antimicrobial activity against a diverse set of pathogens. Using nonviral vectors we have genetically modified the novel, nontumorigenic, pathogen-free human keratinocyte progenitor cell line (NIKS) to express the human cathelicidin HDP in a tissue-specific manner. NIKS skin tissue that expresses elevated levels of cathelicidin possesses key histological features of normal epidermis and displays enhanced antimicrobial activity against bacteria in vitro. Moreover, in an in vivo infected burn wound model, this tissue results in a two log reduction in a clinical isolate of multidrug-resistant Acinetobacter baumannii. Taken together, these results suggest that this genetically engineered human tissue could be applied to burns and ulcers to counteract bacterial contamination and prevent infection.
The Relative Safety of Ephedra Compared with Other Herbal Products
Authors: Stephen Bent, Thomas N. Tiedt, Michelle C. Odden, Michael G. Shlipak
Journal: Annals of Internal Medicine (2003)

Background: Ephedra is widely used in dietary supplements that are marketed to promote weight loss or increase energy; however, the safety of this product has been questioned because of numerous case reports of adverse events. Objective: To compare the risk for adverse events attributable to ephedra and other herbal products. Design: Comparative case series. Setting: American Association of Poison Control Centers Toxic Event Surveillance System Database Annual Report, 2001. Measurements: The relative risk and 95% confidence interval for experiencing an adverse reaction after ephedra use compared with other herbs. This risk was defined as the ratio of adverse reactions to ephedra versus other products, divided by the ratio of their relative use in the United States. Results: Products containing ephedra accounted for 64% of all adverse reactions to herbs in the United States, yet these products represented only 0.82% of herbal product sales. The relative risks for an adverse reaction in persons using ephedra compared with other herbs were extremely high, ranging from 100 (95% CI, 83 to 140) for kava to 720 (CI, 520 to 1100) for Ginkgo biloba. Conclusions: Ephedra use is associated with a greatly increased risk for adverse reactions compared with other herbs, and its use should be restricted.
Synthetic miR-34a Mimics as a Novel Therapeutic Agent for Multiple Myeloma:<i>In Vitro</i>and<i>In Vivo</i>Evidence
Authors: Maria T. Di Martino, Emanuela Leone, Nicola Amodio, Umberto Foresta, Marta Lionetti, Maria R. Pitari, Maria E. Gallo Cantafio, Annamaria Gullà, Francesco Conforti, Eugenio Morelli, Vera Tomaino, Marco Rossi, Massimo Negrini, Manlio Ferrarini, Michele Caraglia, Masood A. Shammas, Nikhil C. Munshi, Kenneth C. Anderson, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone
Journal: Clinical Cancer Research (2012)

Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a.Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo.Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity.Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.