tbuckley/cabot-search huggingface dataset:
PKCδ is required for survival of cells expressing activated p21Ras.
Authors: Shuhua Xia, Lora W. Forman, Douglas V. Faller
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4123 

Previous studies have shown that inhibition of PKC activity in transformed cells and cancer cells containing activated p21Ras results in apoptosis. The molecular basis underlying this process, however, have remained elusive. To gain insight into the mechanism of the apoptotic pathway induced by the p21Ras oncoprotein, we first determined whether inhibition of one specific PKC isozyme was sufficient to initiate apoptosis. Isozyme-specific chemical inhibitors, dominant-negative proteins, and siRNA were employed to inhibit individual PKC isozymes. These studies demonstrated that PKCδ plays the critical role in p21Ras-mediated apoptosis. The p21Ras effector pathways leading to apoptosis were next examined. The PI3K inhibitor (LY294002) partially blocked Ras-mediated apoptosis. In agreement, a constitutively-activated PI3K (p110-CAax) was capable of inducing apoptosis after PKCδ inhibition. In contrast, the other Ras effectors Raf and RIF-CAax (Ral-GEF) induced little apoptosis in cells after treatment with PKCδ-specific inhibitors. The presence of an activating p21Ras mutation, either naturally-occurring or experimentally-induced, increases the expression of PKCδ transcript and protein in mesenchymal and epithelial cells. Conversely, inhibition of p21Ras activity by a farnesyl transferase inhibitor (FPTIII) decreased expression of PKCδ. Activation of the PI3K Ras effector pathway induced PKCδ to the same extent as activated p21Ras. Collectively, our data demonstrates that p21Ras, through its downstream effector PI3K, induces PKCδ expression and that this increase in PKCδ is required for cell survival. Selective suppression of PKCδ activity and consequent induction of apoptosis is a potential strategy for targeting of tumor cells containing an activated p21Ras.
Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy
Authors: T Narita, M Ri, A Masaki, F Mori, A Ito, S Kusumoto, T Ishida, H Komatsu, S Iida
Journal: Blood Cancer Journal (2015)

Abstract Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS&lt;6 months ( n =33) and a second group with PFS⩾6 months ( n =23). Of the 15 genes analyzed, the expression of activating transcription factor 3 ( ATF3 ) and ATF4 was significantly lower in patients with shorter PFS ( P =0.0157 and P =0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa , which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.
Neurological (NEU) and Cytological (CYT) Response (R) As Early Predictors of Time-To-Progression (TTP) and Overall Survival (OS) in Patients (PTS) with Leptomeningeal Carcinomatosis (LMC) Treated with Intrathecal (I.T) Liposomal Cytarabine (LYC)
Authors: J.P. Fusco, E. Castanon Alvarez, L. Zubiri, P. Martín, O.E. Carranza Rua, J. Espinos Jimenez, J. Rodriguez, M. Santisteban, J.M. Aramendia, I. Gil-Bazo
Journal: Annals of Oncology (2012)
Royal Medical Benevolent Fund Christmas appeal
Authors: N Birch, George Porter
Journal: BMJ (1976)

Traces of serious costoclavicular syndesmoses have often been found in ancient populations, and are attributable to the stresses produced by heavy, continuous manual labour, for example the hand-tilling of fields 2 or the rowing of boats. 1 The lesion presents in different ways, from osteolysis limited to the area below the clavicular insertion to the formation of a true fossa which is known as the rhomboid subclavicular fossa. 3 The lesion is typically symmetric when caused by stress that involves equal use of both upper limbs, though it can be asymmetric when the activity only involves one arm—for example in people who guide one-oared boats. 1
Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial
Authors: Jun Imagawa, Hideo Tanaka, Masaya Okada, Hirohisa Nakamae, Masayuki Hino, Kazunori Murai, Yoji Ishida, Takashi Kumagai, Seiichi Sato, Kazuteru Ohashi, Hisashi Sakamaki, Hisashi Wakita, Nobuhiko Uoshima, Yasunori Nakagawa, Yosuke Minami, Masahiro Ogasawara, Tomoharu Takeoka, Hiroshi Akasaka, Takahiko Utsumi, Naokuni Uike, Tsutomu Sato, Sachiko Ando, Kensuke Usuki, Satoshi Morita, Junichi Sakamoto, Shinya Kimura
Journal: The Lancet Haematology (2015)
The early adaptive evolution of calmodulin.
Authors: M L Baba, M Goodman, J Berger-Cohn, J G Demaille, G Matsuda
Journal: Molecular Biology and Evolution (1984)

Interaction between gene duplication and natural selection in molecular evolution was investigated utilizing a phylogenetic tree constructed by the parsimony procedure from amino acid sequences of 50 calmodulin-family protein members. The 50 sequences, belonging to seven protein lineages related by gene duplication (calmodulin itself, troponin-C, alkali and regulatory light chains of myosin, parvalbumin, intestinal calcium-binding protein, and glial S-100 phenylalanine-rich protein), came from a wide range of eukaryotic taxa and yielded a denser tree (more branch points within each lineage) than in earlier studies. Evidence obtained from the reconstructed pattern of base substitutions and deletions in these ancestral loci suggests that, during the early history of the family, selection acted as a transforming force on expressed genes among the duplicates to encode molecular sites with new or modified functions. In later stages of descent, however, selection was a conserving force that preserved the structures of many coadapted functional sites. Each branch of the family was found to have a unique average tempo of evolutionary change, apparently regulated through functional constraints. Proteins whose functions dictate multiple interaction with several other macromolecules evolved more slowly than those which display fewer protein-protein and protein-ion interactions, e.g., calmodulin and next troponin-C evolved at the slowest average rates, whereas parvalbumin evolved at the fastest. The history of all lineages, however, appears to be characterized by rapid rates of evolutionary change in earlier periods, followed by slower rates in more recent periods. A particularly sharp contrast between such fast and slow rates is found in the evolution of calmodulin, whose rate of change in earlier eukaryotes was manyfold faster than the average rate over the past 1 billion years. In fact, the amino acid replacements in the nascent calmodulin lineage occurred at residue positions that in extant metazoans are largely invariable, lending further support to the Darwinian hypothesis that natural selection is both a creative and a conserving force in molecular evolution.
Investigations to diagnose cause of dizziness in elderly people
Authors: S. Caine, M. MacMahon, P. Evans, D. P. Gray, R. Steele, K. Sweeney, N. Colledge, J. Wilson
Journal: BMJ (1997)

Data are not now collected by ethnic group in South AfricaEditor-Claire Hilton notes that since April 1995 British hospitals have had to collect data on each patient's ethnic group. 1 In the United States this is standard practice.In the Morbidity and Mortality Weekly Report data on numerous variables relating to the health and ill health of black and white people are regularly given 2 -as also, on occasion, are data on Hispanics, American Indians, Inuits, and Pacific Islanders.In South Africa precisely the converse has occurred.Ethnic subdivisions have stopped appearing in reports from the Central Statistics Services, and thus mortalities are no longer given for the constituent populations (black, Asian, coloured (Eur-African-Malay), and white), only for the combined population.Additionally, in our big cities annual reports from public health departments provide only combined data on morbidity and mortality.Disadvantages are many.Recently, colleagues and I reviewed changes in the total death rate and the death rate from coronary heart disease in South African populations. 3 We found that, from 1978 to 1989, mortality from coronary heart disease fell by 56% in the white population and by 36% in each of the Indian and coloured populations.Because changes in mortality from this foremost "killer" are continuing we intended to update our information.But this is now precluded.Currently, desegregation does not apply to our national cancer registry.But if it did how, for example, could benefits from Papanicolaou smear tests be assessed?The incidences of cervical cancer in the black and coloured populations are among the highest in the world.The constituent populations of South Africa have a wider divergence in the occurrence of a variety of diseases than occurs in any other country: coronary heart disease, appendicitis, colon cancer, and hip fractures.Interethnic differences in the occurrence of disease, reactivity, and metabolism are well known elsewhere. 4 In South Africa the change to using combined data will make it harder to identify and quantify the target populations who are in most need of help, as well as severely stultifying research on the occurrence of disease and on combating it.Hilton is right, of course, that the level of treatment is affected by ethnic group.Recently, in the United States the effect of race and income on mortality and the use of services among beneficiaries of Medicare was investigated; both race and income were shown as having substantial prejudicial effects, that of race being much more pronounced than that of income. 5This is a matter of universal shame.
Lack of knowledge is not the problem
Authors: D. Brewster
Journal: BMJ (1994)

We report an unusual complication after thrombo- lysis was given to a patient in whom the diagnosis was wrong.A 34 year old man was transferred from a district hospital to our invasive care unit because of haemodynamic instability after thrombolytic treat- ment for acute myocardial infarction.Acute myocardial infarction had been diagnosed on the basis of 1 mm horizontal elevation of the ST segment in leads II and III and AVF and decreased pain after sublingual nitrates.On arrival in the intensive care unit the patient was complaining of epigastric and left upper abdominal pain that radiated to his shoulder.He was pale and sweating, with blood pressure 120/80 mm Hg and pulse rate 130/min.The lungs were clear, and, except for the tachycardia, an examination of the heart yielded normal findings.Curiously, deep abdominal palpation was asso- ciated with moderate pain in the left upper abdomen.An electrocardiogram showed a sinus tachycardia of 120 beats/min.The patient was given intravenous morphine, and his pain disappeared almost completely.
Association of Cole disease with novel heterozygous mutations in the somatomedin-B domains of the<i>ENPP1</i>gene: necessary, but not always sufficient
Authors: N.A. Schlipf, H. Traupe, Y. Gilaberte, W.K. Peitsch, I. Hausser, V. Oji, A. Schmieder, S.W. Schneider, P. Demmer, B. Rösler, J. Fischer
Journal: British Journal of Dermatology (2015)
The epitope associated with the binding of the capsular polysaccharide of the group B meningococcus and of Escherichia coli K1 to a human monoclonal macroglobulin, IgMNOV.
Authors: E A Kabat, J Liao, E F Osserman, A Gamian, F Michon, H J Jennings
Journal: The Journal of Experimental Medicine (1988)

The fine structure of the combining site of human mAb IgMNOV to poly-alpha(2----8)linked NeuNAc, the epitope of the group B meningococcal and E. coli K1 polysaccharides, has been probed using RIA and ELISA. Inhibition by oligomers ranging from 2 to 12 residues was used to assay binding to IgMNOV by group B meningococcal polysaccharide preparations (GBMP) or by poly(A). The inhibitory properties of the oligomers were almost identical in both assays of the binding of GBMP to horse IgM (H46). This evidence and the finding that both GBMP and poly(A) precipitated IgMNOV equally per unit weight indicated that the epitope of poly(A) must mimic an equivalent epitope on GBMP despite the absence of any apparent common structural features in the two molecules. Unlike most carbohydrate-anticarbohydrate systems in which the site is saturated by oligomers of up to six or seven sugars, all the anti-alpha(2----8)NeuNAc systems above required much larger oligomers. Because these oligomers are larger than the maximum size of an antibody site the epitope must be conformationally controlled, and this has been confirmed by nuclear magnetic resonance spectroscopy. However, despite the above similarities, GBMP and poly(A) were differentiated in that only GBMP bound to H46. Smaller linear molecules obtained by delipidating the GBMP, as well as periodate-oxidized GBMP with its nonreducing end oxidized or linked covalently to BSA, bound to and precipitated IgMNOV and H46. This showed that, despite their differences, terminal nonreducing ends were not involved and that both epitopes were located in the conformationally controlled inner residues of the GBMP. The difference thus must reside in the ability of IgMNOV and H46 to recognize different structural aspects of the same conformationally controlled inner residues. The ELISA data indicate that both IgMNOV and H46 have groove-type sites that bind exclusively to an epitope located on the acidic side of the inner residues. The differences determining the ability of IgMNOV and the failure of H46 to cross-react with poly(A), poly(I), and denatured DNA, may depend on differences in the degree of protonation required by each antibody, and this may be clarified by a study of the effects of pH on the precipitin behavior of IgMNOV and H46.
Improvement of a national public health surveillance system through use of a quality circle
Authors: G Krause, J Benzler, G Reiprich, R Görgen
Journal: Eurosurveillance (2006)

Surveillance systems for infectious diseases build the basis for effective public health measures in the prevention and control of infectious diseases. Assessing and improving the quality of such national surveillance systems is a challenge, as many different administrations and professions contribute to a complex system in which sensitive information must be exchanged in a reliable and timely fashion. We conducted a multidisciplinary quality circle on the national public health surveillance system in Germany which included clinicians, laboratory physicians, and staff from local and state health departments as well as from the Robert Koch-Institut. The recommendations resulting from the quality circle included proposals to change the federal law for the control of infectious diseases as well as practical activities such as the change of notification forms and the mailing of faxed information letters to clinicians. A number of recommendations have since been implemented, and some have resulted in measurable improvements. This demonstrates that the applied method of quality circle is a useful tool to improve the quality of national public health surveillance systems.
Effectiveness of Darbepoetin Alfa (Da) for Chemotherapy-Induced Anaemia (Cia) When Initiated at Haemoglobin (Hb) ≤10 G/Dl
Authors: R. Pirker, J.F. Vansteenkiste, M. Hedenus, E. Hernandez, L. Belton, J. Terwey
Journal: Annals of Oncology (2014)
The interaction between CD8+ cytotoxic T cells and Leishmania-infected macrophages.
Authors: L E Smith, M Rodrigues, D G Russell
Journal: The Journal of Experimental Medicine (1991)

Leishmania is resident within the macrophages of its vertebrate host. In any intramacrophage infection, where the pathogen is present in a form capable of mediating cell to cell transmission, the contribution of a cytotoxic T cell response to protective immunity is questionable. This study presents data from an in vitro model designed to elucidate the outcome of an interaction between CD8+, cytotoxic T cells and infected macrophages. Experiments were conducted with an H-2d-restricted, cytotoxic CD8+ T cell clone and Leishmania parasites present in mixed macrophage cultures, with the parasites confined to either histocompatible BALB/c macrophages, or incompatible CBA macrophages. Initial experiments indicated that the viability of Leishmania was unaffected by the lysis of its host macrophage by cytotoxic T cells. However, extended experiments showed that the parasites were killed between 24 and 72 h. The same results were obtained regardless of whether the parasites were resident in the target, BALB/c, macrophages or the bystander, CBA, macrophages. Addition of neutralizing, anti-IFN-g antibody to the cultures ablated most of the leishmanicidal behavior, indicating that parasite death was attributable to macrophage activation, resulting from cytokine secretion from the T cells following the initial recognition event.
Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients
Authors: W. Ray Kim, Thomas Berg, Tarik Asselah, Robert Flisiak, Scott Fung, Stuart C. Gordon, Harry L.A. Janssen, Pietro Lampertico, Daryl Lau, Jeffrey D. Bornstein, Raul E. Aguilar Schall, Phillip Dinh, Leland J. Yee, Eduardo B. Martins, Seng Gee Lim, Rohit Loomba, Jörg Petersen, Maria Buti, Patrick Marcellin
Journal: Journal of Hepatology (2015)
Long term survival in IMAGE 1 (Immune Modulation And Gemcitabine Evaluation 1), a randomized, open-label phase II trial comparing gemcitabine with and without IMM-101 in advanced pancreatic cancer.
Authors: Angus George Dalgleish
Journal: Journal of Clinical Oncology (2015)

3051 Background: Immunotherapy may produce durable responses in some patients. IMM-101, a systemic immunomodulator containing heat-killed Mycobacterium obuense (NCTC13365), can be combined with various forms of chemotherapy and has shown survival benefits in cancer patients. Methods: In IMAGE 1, survival, safety and tolerability were assessed in advanced pancreatic cancer patients (n = 110) with a WHO score of 0-2 receiving IMM-101 (0.1 mL, 10 mg/mL intradermally) + Gemcitabine (Gem) (1000 mg/m2 q7d3) (n = 75) or Gem alone (n = 35) for a 12-cycle maximum. Patients who completed IMAGE 1 were invited to enter a follow-up study to monitor long term survival, and received IMM-101 and, at the investigator's discretion, adjunctive chemotherapy. Results: As previously reported, IMM-101 was associated with clinically meaningful increases in OS and PFS, with no additional burden of adverse events above those relating to chemotherapy or the underlying disease. Patients in the ITT set with metastatic disease (n = 92) benefited most with a significant increase in median OS from 4.4 months in the Gem group (n = 28) to 7 months in the IMM-101 + Gem group (n = 64) (p = 0.01; HR 0.54, 95% CI 0.33-0.87). We now report an increase in survival probability at 12 months from 11.5% in the Gem group to 22.4% in the IMM-101 + Gem group. Consistent with an increasing separation of the K-M curves, this is amplified at 18 months when the figures are 2.3% and 18.3% in the respective groups. The times corresponding to 25% probability of survival are 7.2 and 11.5 months for the Gem and IMM-101 + Gem group, respectively, an extension of 4.3 months. Of 11 metastatic patients in the ongoing follow-up study, all from the IMM-101 + Gem group, 8 survived for 18 months from randomization and 4 of these remained alive at 2 years. The longest period on study is currently 34 months. Conclusions: First line IMM-101 with adjunctive chemotherapy produced significant survival benefits in patients with metastatic disease. The durable responses seen in a proportion of patients are consistent with immunotherapy for other cancers but were not predicted in advanced pancreatic cancer. Clinical trial information: NCT01303172.
CIRCUS: a kiss of death for cardioprotection?
Authors: Gerd Heusch
Journal: Cardiovascular Research (2015)

Cardioprotection is a relatively vague term which more specifically refers to all interventions that reduce myocardial ischemia/reperfusion injury.1 In experimental animals, the most robust endpoint for such cardioprotection is a reduction in infarct size in relation to the area at risk. In patients, area at risk and infarct size are more difficult to determine (from cardiac enzyme release and imaging), and clinical outcome is the most relevant endpoint. Apart from cardioprotection by hypothermia and cardioplegia in surgical settings, the various conditioning phenomena and a number of drugs which recruit signalling steps of the conditioning phenomena have been studied in thousands of experimental studies over the last 30 years.2 Mechanistically, the mitochondria, and more specifically the mitochondrial permeability transition pore (MPTP), have emerged as most critical subcellular signalling elements of cardioprotection.3

Cyclosporine A is not only immunosuppressive through inhibition of calcineurin but also binds to cyclophilin D which is essential for opening of the MPTP4 and thereby reduces infarct size in mice,5,6 rats,7,8 rabbits,9,10 and pigs.11,12 Of note, however, not all experimental studies were positive.13–16 A pioneering proof-of-concept trial was published …
Chromosomal location of the structural gene cluster encoding murine immunoglobulin heavy chains.
Authors: P D'Eustachio, D Pravtcheva, K Marcu, F H Ruddle
Journal: The Journal of Experimental Medicine (1980)

To determine the chromosomal location of mouse immunoglobulin heavy chain structural genes unambiguously, a panel of somatic cell hybrids was scored for the presence of DNA sequences homologous to gamma 2b-, mu-, and alpha-heavy chain-constant region DNA probe molecules. The hybrids, formed between mouse and hamster cells, contained various combinations of mouse chromosomes plus a full set of hamster chromosomes. Hybrids that retained mouse chromosome 12 reacted with the probes, whereas hybrids that had lost the chromosome, or its distal half, failed to react. These results indicate that structural genes for the gamma 2b-, mu-, and alpha-heavy chain-constant regions map to the distal half of this chromosome.