tbuckley/cabot-search huggingface dataset:
Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors
Authors: By Zhao, John P Vasilakos, Debra Tross, Dmitri Smirnov, Dennis M Klinman
Journal: Journal for ImmunoTherapy of Cancer (2014)

The TLR7/8 agonist 3M-052 and the TLR9 agonist CpG ODN both trigger innate immune responses that support the induction of tumor-specific immunity. Previous studies showed that these agonists used individually could improve the survival of mice challenged with small tumors but were of limited therapeutic benefit against large/advanced tumors.Normal mice were challenged with syngeneic tumors. Once these tumors reached clinically detectable size (500-800 mm(3)) they were treated by intra-tumoral injection with 3M-052 and/or CpG ODN. Anti-tumor immunity and tumor growth were evaluated.The co-delivery of agonists targeting TLRs 7, 8 and 9 increased the number and tumoricidal activity of tumor infiltrating CTL and NK cells while reducing the frequency of immunosuppressive MDSC. The combination of 3M-052 plus CpG ODN (but not each agent alone) eradicated large primary tumors and established long-term protective immunity.The combination of agonists targeting TLRs 7/8 and 9 represents a significant improvement in cancer immunotherapy.
Dealing With a Deluge of Data: An Assessment of Adverse Event Data on North Central Cancer Treatment Group Trials
Authors: Michelle R. Mahoney, Daniel J. Sargent, Michael J. O'Connell, Richard M. Goldberg, Paul Schaefer, Jan C. Buckner
Journal: Journal of Clinical Oncology (2005)

Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non-life-threatening events. We assessed the utility of the RAE data collected, relative to the volume.We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials.A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial.The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.
ATS/ERS/WASOG statement on sarcoidosis
Authors: U. Costabel, G.W. Hunninghake, None on behalf of the Sarcoidosis Statement Committee
Journal: European Respiratory Journal (1999)

The first international consensus statement on sarcoidosis is currently being copublished in the journals of the American Thoracic Society (ATS) and the World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG) [1,2].This editorial wants to attract the attention of the ERJ readers and European Respiratory Society (ERS) members to this consensus report which is aimed at updating clinicians and scientists about new advances related to sarcoidosis.It is hoped that the document will improve the care of patients with this disorder and trigger new studies to further elucidate the cause and pathogenesis of sarcoidosis.The panel members are experts in the care of patients with sarcoidosis, and the level of evidence for the recommendations made in this statement is largely that of expert opinion developed by consensus.There is little supportive evidence from wellconducted randomized controlled trials.The panel agreed on the following consensus of the state of the art of the understanding of pathogenesis, diagnosis, and treatment of sarcoidosis:What we know: N The clinical features and syndromes N How to make a diagnosis N That corticosteroids are an effective short-term therapy N The incidence and prevalence of the disease N That some genetic factors alter expression of the disease N The immunology characteristic of the initial onset of the disease.What we would like to know: N If there is a test to predict progression N If corticosteroids alter the natural history of the disease N The optimal length of therapy N If there are less toxic therapies than corticosteroids or cytotoxic agents N How genetic factors alter expression of the disease N If genetic factors affect susceptibility to the disease N The mechanisms of lung injury and fibrosis N The mechanisms that result in persistent disease N The cause of sarcoidosis.The panel was divided into groups responsible for writing specific sections of the statement dealing with definition, history, epidemiology, aetiology and pathogenesis, pathology, clinical presentation and organ involvement, diagnostic approaches, natural history, and treatment of sarcoidosis.The following is a summary of some of the sentinal statements of these sections.The epidemiology of sarcoidosis remains problematic for several reasons, including: 1) lack of a precise, consistent case definition; 2) variable methods of case ascertainment; 3) variability in disease presentation; 4) lack of
Two Evolutionarily Distinct Classes of Paleopolyploidy
Authors: Olivier Garsmeur, James C. Schnable, Ana Almeida, Cyril Jourda, Angélique D’Hont, Michael Freeling
Journal: Molecular Biology and Evolution (2013)

Whole genome duplications (WGDs) occurred in the distant evolutionary history of many lineages and are particularly frequent in the flowering plant lineages. Following paleopolyploidization in plants, most duplicated genes are deleted by intrachromosomal recombination, a process referred to as fractionation. In the examples studied so far, genes are disproportionately lost from one of the parental subgenomes (biased fractionation) and the subgenome having lost the lowest number of genes is more expressed (genome dominance). In the present study, we analyzed the pattern of gene deletion and gene expression following the most recent WGD in banana (alpha event) and extended our analyses to seven other sequenced plant genomes: poplar, soybean, medicago, arabidopsis, sorghum, brassica, and maize. We propose a new class of ancient WGD, with Musa (alpha), poplar, and soybean as members, where genes are both deleted and expressed to an equal extent (unbiased fractionation and genome equivalence). We suggest that WGDs with genome dominance and biased fractionation (Class I) may result from ancient allotetraploidies, while WGDs without genome dominance or biased fractionation (Class II) may result from ancient autotetraploidies.
Non Conservation of Function for the Evolutionarily Conserved Prdm1 Protein in the Control of the Slow Twitch Myogenic Program in the Mouse Embryo
Authors: Stéphane D. Vincent, Alicia Mayeuf, Claire Niro, Mitinori Saitou, Margaret Buckingham
Journal: Molecular Biology and Evolution (2012)

Muscles are composed of multinucleated muscle fibers with different contractile and physiological properties, which result from specific slow or fast gene expression programs in the differentiated muscle cells. In the zebra fish embryo, the slow program is under the control of Hedgehog signaling from the notochord and floor plate. This pathway activates the expression of the conserved transcriptional repressor, Prdm1 (Blimp1), which in turn represses the fast program and promotes the slow program in adaxial cells of the somite and their descendants. In the mouse embryo, myogenesis is also initiated in the myotomal compartment of the somite, but the slow muscle program is not confined to a specific subset of cells. We now show that Prdm1 is expressed in the first differentiated myocytes of the early myotome from embryonic day (E)9.5-E11.5. During this period, muscle formation depends on the myogenic regulatory factors, Myf5 and Mrf4. In their absence, Prdm1 is not activated, in apparent contrast to zebra fish where Prdm1 is expressed in the absence of Myf5 and MyoD that drive myogenesis in adaxial cells. However, as in zebra fish, Prdm1 expression in the mouse myotome does not occur in the absence of Hedgehog signaling. Analysis of the muscle phenotype of Prdm1 mutant embryos shows that myogenesis appears to proceed normally. Notably, there is no requirement for Prdm1 activation of the slow muscle program in the mouse myotome. Furthermore, the gene for the transcriptional repressor, Sox6, which is repressed by Prdm1 to permit slow muscle differentiation in zebra fish, is not expressed in the mouse myotome. We propose that the lack of functional conservation for mouse Prdm1, that can nevertheless partially rescue the adaxial cells of zebra fish Prdm1 mutants, reflects differences in the evolution of the role of key regulators such as Prdm1 or Sox6, in initiating the onset of the slow muscle program, between teleosts and mammals.
Hereditary deficiency of the fifth component of complement in man. I. Clinical, immunochemical, and family studies.
Authors: S I Rosenfeld, M E Kelly, J P Leddy
Journal: Journal of Clinical Investigation (1976)

The first recognized human kindred with hereditary deficiency of the fifth component of complement (C5) is described. The proband, a 20-year-old black female with systemic lupus erythematosus since age 11, lacked serum hemolytic complement activity, even during remission. C5 was undetectable in her serum by both immunodiffusion and hemolytic assays. Other complement components were normal during remission of lupus, but C1, C4, C2, and C3 levels fell during exacerbations. A younger half-sister, who had no underlying disease, was also found to lack immunochemically detectable C5. By hemolytic assay, she exhibited 1-2% of the normal serum C5 level and normal concentrations of other complement components. C5 levels of other family members were either normal or approximately half-normal, consistent with autosomal codominant inheritance of the gene determining C5 deficiency. Normal hemolytic titers were restored to both homozygous C5-deficient (C5D) sera by addition of highly purified human C5. In specific C5 titrations, however, it was noted that when limited amounts of C5 were assayed in the presence of low dilutions of either C5D serum, curving rather than linear dose-response plots were consistently obtained, suggesting some inhibitory effect. Further studies suggested that low dilutions of C5D serum contain a factor (or factors) interfering at some step in the hemolytic assay of C5, rather than a true C5 inhibitor or inactivator. Of clinical interest are (a) the documentation of membranous glomerulonephritis, vasculitis, and arthritis in an individual lacking C5 (and its biologic functions), and (b) a remarkable propensity to bacterial infections in the proband, even during periods of low-dose or alternate-day corticosteroid therapy. Other observations indicate that the C5D state is compatible with normal coagulation function and the capacity to mount a neutrophilic leukocytosis during pyogenic infection.
Transforming Growth Factor β Production Is Inversely Correlated with Severity of Murine Malaria Infection
Authors: Fakhereldin M. Omer, Eleanor M. Riley
Journal: The Journal of Experimental Medicine (1998)

We have examined the role of the immunomodulatory cytokine transforming growth factor (TGF)-β in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-β, and production of bioactive TGF-β by splenocytes, were found to be low in lethal infections with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-β production. A causal association between the failure to produce TGF-β and the severity of malaria infection was demonstrated by treatment of infected mice with neutralizing antibody to TGF-β, which exacerbated the virulence of P. berghei and transformed a resolving P. chabaudi chabaudi infection into a lethal infection, but had little effect on the course of P. yoelii infection. Parasitemia increased more rapidly in anti–TGF-β–treated mice but this did not seem to be the explanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei–infected mice with recombinant TGF-β (rTGF-β) slowed the rate of parasite proliferation and prolonged their survival from 15 to up to 35 d. rTGF-β treatment was accompanied by a significant decrease in serum tumor necrosis factor α and an increase in interleukin 10. Finally, we present evidence that differences in TGF-β responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-β. Thus, TGF-β seems to induce protective immune responses, leading to slower parasite growth, early in infection, and, subsequently, appears to downregulate pathogenic responses late in infection. This duality of effect makes TGF-β a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.
A CRITIQUE OF PSYCHIATRIC AND PSYCHOLOGICAL RESEARCH ON INSULIN TREATMENT IN SCHIZOPHRENIA
Authors: HENRY P. DAVID
Journal: American Journal of Psychiatry (1954)

After twenty years of research with insulin treatment in schizophrenia the published evidence is inconclusive and contradictory. Wide variations in remission and recovery have been reported but the number of published control studies is meagre. Psychological tests yield no definitive data on prognosis or the effects of treatment. Insulin treatment in schizophrenia continues to pose a major challenge to research.
THE THERAPEUTIC SIGNIFICANCE OF FEAR IN THE METRAZOL TREATMENT OF SCHIZOPHRENIA
Authors: Louis H. Cohen
Journal: American Journal of Psychiatry (1939)

A method is described in which a physiological state, similar to if not identical with "fear" is induced. It has been employed in a series of 20 cases to investigate and compare the relative therapeutic significance of "fear" with the usual convulsant procedure in the metrazol treatment of schizophrenia. The method consists essentially of the slow intravenous injection of minimal amounts of metrazol. The "fear" states induced in this manner have a duration of a few minutes to several hours. The incidence of convulsive seizures can in this manner be fairly well controlled. In a group of 20 schizophrenic patients in whom this procedure was carried out on 10 successive days the therapeutic outcome after 1 month was compared with the same group treated with 10 daily convulsive seizures. The "fear of treatment" characterizing some patients was also studied in both procedures. It was shown that the procedure with "induced fear" was of less therapeutic value than that characterized by convulsions. Furthermore, the "fear of treatment" which has been differentiated from "induced fear" was again shown to be of little or no therapeutic significance.
Invasive Prostate Carcinoma Driven by c-Src and Androgen Receptor Synergy
Authors: Houjian Cai, Ivan Babic, Xiao Wei, Jiaoti Huang, Owen N. Witte
Journal: Cancer Research (2010)

Cellular Src (c-Src) integrates a large number of signal transduction pathways regulating cell division, migration, and other aspects of cell physiology. Mutations of Src kinase have not been described in human prostate cancer, but evidence for increased levels of expression accompanying cancer progression has been reported. We analyzed overexpression of c-Src in naïve mouse prostate epithelium and observed no change in tubule formation frequency or histologic structure. However, when enhanced c-Src expression is coupled with enhanced expression of androgen receptor (AR), it results in a strong activation of Src kinase activity accompanied by activation of the MAPK pathway, and enhanced AR activity. Similar to the pathology induced by constitutively active c-Src(Y529F), the tubules progress to frank carcinoma with invasion and display markers of epithelial-to-mesenchymal transition. These combined results suggest that nonmutated Src kinase may play a more important role in the genesis and progression of prostate cancer than previously appreciated and that epigenetic changes that enhance the level of AR may select for enhanced expression of c-Src with accompanying activation and a strong drive to malignant progression.
Anti-doping activites of volleyball in Japan
Authors: Y Hashimoto, T Yamashita, Y Hamu, M Hayashi
Journal: British Journal of Sports Medicine (2011)

Background Anti-doping activities are necessary for justice and fairness in sports. In and out of competition doping tests are now mainly responsible for anti-doping activities. Objective To clarify the anti-doping activities in Japan in recent years. Design, setting, and participants The object of the investigation is to summarize the doping tests performed after the volleyball games in Japan between 2006–2009. The anti-doping activities were mainly in the responsibility of the anti-doping subcommittee of the Japan Volleyball Association. This subcommittee is doing the coordination of drug testing in international games and domestic games. The competitions in which the doping tests were done were international games (Volleyball World Championship (VWC), World Cup (WC), World Grand Prix (WGP), Grand Champions Cup (GCC), and final preliminary qualifying contests (OQT) for the Olympic Games), and domestic games (V League, Emperor's Cup, and national constitution). Undergo doping test athletes were randomly chosen by lot from among all the participating players of the competition. Out-of-competition testing was based on the information ADAMS and whereabouts. All tests were urine, blood tests were not performed. All samples were carried to Mitsubishi Chemical Medience that was the only WADA official recognition analyzing facilities in Japan. Results The number of samples increased every year, and the out of competition testing became a higher percentage of the total number of samples. The number of tests each year are as follows. Conclusions There are many international games, and are many chances of the doping tests in Japan. Recently, the number of OOCT is increased. The most import ant thing is to raise awareness of anti-doping to individual players through the tests and the educational activities. View this table:
Dominant-Negative Histone H3 Lysine 27 Mutant Derepresses Silenced Tumor Suppressor Genes and Reverses the Drug-Resistant Phenotype in Cancer Cells
Authors: Phillip H. Abbosh, John S. Montgomery, Jason A. Starkey, Milos Novotny, Eleanor G. Zuhowski, Merrill J. Egorin, Annie P. Moseman, Adam Golas, Kate M. Brannon, Curtis Balch, Tim H.M. Huang, Kenneth P. Nephew
Journal: Cancer Research (2006)

Abstract Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes. One such histone modification, particularly at H3 and H4, is methylation at specific lysine (K) residues. Whereas histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 have been reported. Here, we generated a stable cell line overexpressing a dominant-negative point mutant, H3-K27R, to examine the role of that specific lysine in ovarian cancer. Expression of this construct resulted in loss of methylation at H3-K27, global reduction of DNA methylation, and increased expression of tumor suppressor genes. One of the affected genes, RASSF1, was shown to be a direct target of H3-K27 methylation–mediated silencing. By increasing DNA-platinum adduct formation, indicating increased access of the drug to target DNA sequences, removal of H3-K27 methylation resensitized drug-resistant ovarian cancer cells to the chemotherapeutic agent cisplatin. This increased platinum-DNA access was likely due to relaxation of condensed chromatin. Our results show that overexpression of mutant H3-K27 in mammalian cells represents a novel tool for studying epigenetic mechanisms and the Histone Code Hypothesis in human cancer. Such findings show the significance of H3-K27 methylation as a promising target for epigenetic-based cancer therapies. (Cancer Res 2006; 66(11): 5582-91)
DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia
Authors: Elaine Willmore, Sarah L. Elliott, Tryfonia Mainou-Fowler, Geoffrey P. Summerfield, Graham H. Jackson, Fran O'Neill, Christopher Lowe, Anthony Carter, Robert Harris, Andrew R. Pettitt, Celine Cano-Soumillac, Roger J. Griffin, Ian G. Cowell, Caroline A. Austin, Barbara W. Durkacz
Journal: Clinical Cancer Research (2008)

Abstract Purpose: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL. Experimental Design: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNA-PKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441 on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of γH2AX). Results: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser2056. High DNA-PK levels predicted for reduced treatment-free interval. Conclusions: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.
Emerging Treatment Options for B-Cell Lymphomas
Authors: Andrew D. Zelenetz
Journal: Journal of the National Comprehensive Cancer Network (2015)

As targeted therapy in B-cell lymphomas rapidly expands beyond anti-CD20 monoclonal antibodies, many newer types of agents are in various stages of development. During his presentation at the NCCN 20th Annual Conference, Dr. Andrew D. Zelenetz explored many of them, including the newer immunoconjugates, the Bruton's tyrosine kinase inhibitor ibrutinib, agents targeting apoptosis such as venetoclax (ABT-199), the immunomodulator lenalidomide, and novel immune checkpoint inhibitors such as nivolumab. To improve outcomes in patients with B-cell lymphomas, these therapies either target the tumor cells and their pathways or focus on the microenvironment and immune modulation.