tbuckley/cabot-search huggingface dataset:
Programmed death 1 blockade, an Achilles heel for MMR-deficient tumors?
Authors: Andy Yingjie Lin, Edward Lin
Journal: Journal of Hematology & Oncology (2015)

Program death receptor-1 (PD-1) is upregulated in many tumors and in tumor microenvironment, and PD-1 blockade has led to remarkable immune-based anti-tumor responses in across many tumor types. Pembrolizumab, an anti-programmed death 1 checkpoint inhibitor, resulted in a high rate of immune response in 41 patients with previously treated mismatch repair (MMR)-deficient tumor including colorectal cancer but not in MMR-stable tumor with expectant toxicities. Both immune-based progression-free and overall survival are quite promising and correlate with high mutation loads in the tumor. MMR-deficient tumors made up not an insignificant proportion of GI and GU cancers and are found mostly in younger patients who had better prognosis than MMR-stable tumors. However, MMR-deficient tumors do not respond to cytotoxic chemotherapy as these agents may require intact DNA mismatch repair to be effective. MMR deficiency occurred as a result of mutations in defined DNA repair complex mutations or epigenetics modifications and gene upstream of DNA repair complex. PD-1 blockade represents our first successful shot at one of the Achilles heels of this MMR-deficient tumor goliath. Only coordinated attack on all of its Achilles heels and healing mechanisms can this tumor Goliath be brought down to its knees.
Improving the Management of Chronic Disease at Community Health Centers
Authors: Bruce E. Landon, LeRoi S. Hicks, A. James O'Malley, Tracy A. Lieu, Thomas Keegan, Barbara J. McNeil, Edward Guadagnoli
Journal: New England Journal of Medicine (2007)

The Health Disparities Collaboratives of the Health Resources and Services Administration (HRSA) were designed to improve care in community health centers, where many patients from ethnic and racial minority groups and uninsured patients receive treatment.We performed a controlled preintervention and postintervention study of community health centers participating in quality-improvement collaboratives (the Health Disparities Collaboratives sponsored by the HRSA) for the care of patients with diabetes, asthma, or hypertension. We enrolled 9658 patients at 44 intervention centers that had participated in the collaboratives and 20 centers that had not participated (external control centers). Each intervention center also served as an internal control for another condition. Quality measures were abstracted from medical records at each health center. We created overall quality scores by standardizing and averaging the scores from all of the applicable measures. Changes in quality were evaluated with the use of hierarchical regression models that controlled for patient characteristics.Overall, the intervention centers had considerably greater improvement than the external and internal control centers in the composite measures of quality for the care of patients with asthma and diabetes, but not for those with hypertension. As compared with the external control centers, the intervention centers had significant improvements in the measures of prevention and screening, including a 21% increase in foot examinations for patients with diabetes, and in disease treatment and monitoring, including a 14% increase in the use of antiinflammatory medication for asthma and a 16% increase in the assessment of glycated hemoglobin. There was no improvement, however, in any of the intermediate outcomes assessed (urgent care or hospitalization for asthma, control of glycated hemoglobin levels for diabetes, and control of blood pressure for hypertension).The Health Disparities Collaboratives significantly improved the processes of care for two of the three conditions studied. There was no improvement in the clinical outcomes studied.
Interleukin 4 (B cell stimulatory factor 1) can mediate the induction of lymphokine-activated killer cell activity directed against fresh tumor cells.
Authors: J J Mulé, C A Smith, S A Rosenberg
Journal: The Journal of Experimental Medicine (1987)

Interleukin 4 (IL-4) expresses multiple biologic activities, including B cell, mast cell, and T cell stimulation. We showed that the incubation of resting splenocytes from C57BL/6 mice solely in purified native or recombinant mouse IL-4 results in the generation of lymphokine-activated killer (LAK) activity directed against fresh, syngeneic sarcoma cells. The precursor activated by IL-4 expresses surface asialo-GM1. In addition, IL-4 is capable of amplifying the splenic LAK activity induced by recombinant IL-2. The generation, by IL-4, of killer cells with broad antitumor reactivity raises the possibility of using IL-4 alone or in combination with IL-2 in the immunotherapy of cancer in animal models.
Erythrocyte Rh antigens increase with red cell age
Authors: Samir K. Ballas, John C. Flynn, Lucy A. Pauline, Darci L. Murphy
Journal: American Journal of Hematology (1986)

Certain blood group antigens may play a role in the removal of senescent red cells from the circulation. In order to elucidate this hypothesis, we have investigated the effect of red cell aging on Rh blood group antigens. Red cells from volunteer donors were separated into subpopulations of uniformly defined densities on discontinuous Stractan density gradients. The number of the five major Rh antigen sites of each fraction was determined both by enzyme-linked immunosorbent assay (ELISA) and by hemagglutination-scoring technique. All Rh antigens tested increased with cell age (p less than 0.01). The data indicate that there is a positive correlation between red cell age and the Rh blood group antigen site number.
<i>Drosophila</i> Models of Neurodegenerative Diseases
Authors: Bingwei Lu, Hannes Vogel
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases.
Influence of electrical axis of stimulation on excitation of cardiac muscle cells.
Authors: L Tung, N Sliz, M R Mulligan
Journal: Circulation Research (1991)

Orthogonal sequential shock can defibrillate the heart with greater efficacy compared with single shock defibrillation. In this study we tested the hypothesis that cardiac cells have a preferred orientation in their response to excitatory extracellular electric fields, so that orthogonal shocks may stimulate distinct populations of cells. A micropaddle electrode system was used to deliver rectangular pulses for extracellular field stimulation of individual heart cells. We found that single frog and guinea pig ventricular myocytes are excitable with rectangular pulse field stimulation over a wide range of pulse durations, ranging from 10 msec to as little as 20 microseconds. The excitation field strength varies inversely with pulse duration as described by the Weiss-Lapicque equation, although the frog myocytes show a significant "notch" at pulse durations of approximately 1-2 msec, and the guinea pig myocytes are more excitable than predicted for pulse durations of less than 0.2 msec. Every myocyte tested was more excitable when the long axis of the cell was oriented parallel to the stimulating field than when perpendicular to the field. For 2-msec pulses, the difference in field strength was a factor of 5.8 +/- 2.0 (n = 30) for frog and 2.6 +/- 0.5 (n = 23) for guinea pig myocytes. Complete excitation strength-duration curves were obtained in seven frog and 14 guinea pig cells for both parallel and perpendicular cell orientations.(ABSTRACT TRUNCATED AT 250 WORDS)
Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis
Authors: Ioanna Nikitopoulou, Nikos Oikonomou, Emmanuel Karouzakis, Ioanna Sevastou, Nefeli Nikolaidou-Katsaridou, Zhenwen Zhao, Vassilis Mersinias, Maria Armaka, Yan Xu, Masayuki Masu, Gordon B. Mills, Steffen Gay, George Kollias, Vassilis Aidinis
Journal: The Journal of Experimental Medicine (2012)

Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.
Keratin mutation primes mouse liver to oxidative injury
Authors: Qin Zhou, Xuhuai Ji, Lixin Chen, Harry B. Greenberg, Shelly C. Lu, M. Bishr Omary
Journal: Hepatology (2005)

Mutation of the cytoskeletal intermediate filament proteins keratin 8 and keratin 18 (K8/K18) is associated with cirrhosis in humans, whereas transgenic mice that overexpress K18 Arg89→Cys (R89C) have significant predisposition to liver injury. To study the mechanism of keratin-associated predisposition to liver injury, we used mouse microarrays to examine genetic changes associated with hepatocyte keratin mutation and assessed the consequences of such changes. Liver gene expression was compared in R89C versus nontransgenic or wild-type K18-overexpressing mice. Microarray-defined genetic changes were confirmed by quantitative polymerase chain reaction. Nineteen genes had a more than two-fold altered expression (nine downregulated, 10 upregulated). Upregulated genes in keratin-mutant hepatocytes included the oxidative metabolism genes cytochrome P450, S-adenosylhomocysteine (SAH) hydrolase, cysteine sulfinic acid decarboxylase, and oxidation-reduction pathway genes. Downregulated genes included fatty acid binding protein 5, cyclin D1, and some signaling molecules. Several methionine metabolism-related and glutathione synthetic pathway intermediates, including S-adenosylmethionine (SAMe) and SAH, were modulated in R89C versus control mice. R89C livers had higher lipid and protein oxidation by-products as reflected by increased malondialdehyde and oxidized albumin. In conclusion, K18 point mutation in transgenic mice modulates several hepatocyte oxidative stress-related genes and leads to lipid and protein oxidative by-products. Mutation-associated decreases in SAH and SAMe could compromise needed cysteine availability to generate glutathione during oxidative stress. Hence keratin mutations may prime hepatocytes to oxidative injury, which provides a new potential mechanism for how keratin mutations may predispose patients to cirrhosis. (HEPATOLOGY 2005;41:517–525.)
The Evolution of Controlled Multitasked Gene Networks: The Role of Introns and Other Noncoding RNAs in the Development of Complex Organisms
Authors: John S. Mattick, Michael J. Gagen
Journal: Molecular Biology and Evolution (2001)

Eukaryotic phenotypic diversity arises from multitasking of a core proteome of limited size. Multitasking is routine in computers, as well as in other sophisticated information systems, and requires multiple inputs and outputs to control and integrate network activity. Higher eukaryotes have a mosaic gene structure with a dual output, mRNA (protein-coding) sequences and introns, which are released from the pre-mRNA by posttranscriptional processing. Introns have been enormously successful as a class of sequences and comprise up to 95% of the primary transcripts of protein-coding genes in mammals. In addition, many other transcripts (perhaps more than half) do not encode proteins at all, but appear both to be developmentally regulated and to have genetic function. We suggest that these RNAs (eRNAs) have evolved to function as endogenous network control molecules which enable direct gene-gene communication and multitasking of eukaryotic genomes. Analysis of a range of complex genetic phenomena in which RNA is involved or implicated, including co-suppression, transgene silencing, RNA interference, imprinting, methylation, and transvection, suggests that a higher-order regulatory system based on RNA signals operates in the higher eukaryotes and involves chromatin remodeling as well as other RNA-DNA, RNA-RNA, and RNA-protein interactions. The evolution of densely connected gene networks would be expected to result in a relatively stable core proteome due to the multiple reuse of components, implying that cellular differentiation and phenotypic variation in the higher eukaryotes results primarily from variation in the control architecture. Thus, network integration and multitasking using trans-acting RNA molecules produced in parallel with protein-coding sequences may underpin both the evolution of developmentally sophisticated multicellular organisms and the rapid expansion of phenotypic complexity into uncontested environments such as those initiated in the Cambrian radiation and those seen after major extinction events.
Clinical presentations and outcome of severe acute respiratory syndrome in children
Authors: KLE Hon, CW Leung, WTF Cheng, PKS Chan, WCW Chu, YW Kwan, AM Li, NC Fong, PC Ng, MC Chiu, CK Li, JS Tam, TF Fok
Journal: The Lancet (2003)

Hong Kong has been severely affected by severe acute respiratory syndrome (SARS). Contact in households and healthcare settings is thought to be important for transmission, putting children at particular risk. Most data so far, however, have been for adults. We prospectively followed up the first ten children with SARS managed during the early phase of the epidemic in Hong Kong. All the children had been in close contact with infected adults. Persistent fever, cough, progressive radiographic changes of chest and lymphopenia were noted in all patients. The children were treated with high-dose ribavirin, oral prednisolone, or intravenous methylprednisolone, with no short-term adverse effects. Four teenagers required oxygen therapy and two needed assisted ventilation. None of the younger children required oxygen supplementation. Compared with adults and teenagers, SARS seems to have a less aggressive clinical course in younger children.
Richard Michael ("Mike") Burton
Authors: R. Britt
Journal: BMJ (2003)

Consultant obstetrician and gynaecologist Hillingdon and Ealing Hospitals 1968-88 (b Staffordshire 1926; q Sheffield 1954; MD, CStJ, TD), died from heart failure and renal failure on 31 March 2003.​2003.




Figure 1




Michael spent a brief period as a “Bevan boy” working in coalmines before joining the Royal Air Force. He trained as a bomber pilot and did an engineering degree at Durham University with the RAF. Michael started medical training in Sheffield in 1948 and on qualifying won a scholarship to work in Albany, New York state. He gained postgraduate degrees at Cambridge in anatomy and physiology. A member of the Territorial Army, he eventually commanded 257(S) General Hospital, and was St John Ambulance area surgeon for London. He leaves a second wife, Toni; three children; and seven grandchildren.
Early Diagnosis of Rocky Mountain Spotted Fever
Authors: Richard D. DeShazo
Journal: JAMA (1976)

Diagnosis of Rocky Mountain spotted fever was made as early as the fourth day of febrile illness in rhesus monkeys (Macaca mulatta), with a monocyte culture technique that is easily amenable to use in humans. Rickettsia rickettsii were identified by direct immunofluorescent and Gimenez staining of cultures of circulating monocytes from four experimentally infected monkeys, even in the presence of a mild or inapparent disease in three. Levels of rickettsemia were estimated by the plaque-assay technique, and specific antibody titers were determined by complement fixation.
Novel transglutaminase inhibitors reverse the inflammation of allergic conjunctivitis
Authors: Joonhong Sohn, Tae-Im Kim, Young-Hee Yoon, Joo-Yong Kim, Soo-Youl Kim
Journal: Journal of Clinical Investigation (2003)

Steroidal anti-inflammatory drugs induce proteins that inhibit phospholipase A(2) (PLA(2)), including uteroglobin and lipocortin-1 (annexin I). Uteroglobin and lipocortin-1 retain several conserved sequences. Based on these sequences, several nonapeptides (antiflammins) were synthesized. These nonapeptides were shown to have anti-inflammatory effects in vitro and in vivo, possibly by inhibiting PLA(2). Subsequent research showed that PLA(2) is activated by transglutaminase 2 (TGase 2). We hypothesize here that TGase 2 inhibitors may increase the anti-inflammatory efficacy of inhibiting PLA(2) activity. To test this theory, we constructed recombinant peptides containing sequences from pro-elafin (for inhibition of TGase 2), and from lipocortin-1, lipocortin-5, and uteroglobin (for inhibition of PLA(2)). The recombinant peptides, which had dual inhibitory effects on purified TGase 2 and PLA(2), reversed the inflammation of allergic conjunctivitis to ragweed in a guinea pig model. The present work suggests that novel recombinant peptides may be safe and effective agents for the treatment of various inflammatory diseases.
Impaired early B cell tolerance in patients with rheumatoid arthritis
Authors: Jonathan Samuels, Yen-Shing Ng, Claire Coupillaud, Daniel Paget, Eric Meffre
Journal: The Journal of Experimental Medicine (2005)

Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35–52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.
High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response.
Authors: S R Nahill, R M Welsh
Journal: The Journal of Experimental Medicine (1993)

Polyclonal stimulation of CD8+ cytotoxic T lymphocytes (CTL) occurs during infection with many viruses including those not known to transform CTL or encode superantigens. This polyclonal CTL response includes the generation of high levels of allospecific CTL directed against many class I haplotypes. In this report we investigated whether the allospecific CTL generated during an acute lymphocytic choriomeningitis virus (LCMV) infection of C57BL/6 mice were stimulated specifically by antigen recognition or nonspecifically by polyclonal mechanisms possibly involving lymphokines or superantigens. An examination of the ability of different strains of mice to induce high levels of CTL specific for a given alloantigen showed that most, but not all, strains generated high levels of allospecific CTL, and that their abilities to generate them mapped genetically to the major histocompatibility complex locus, exclusive of the class II region. This indicated that the virus-induced allospecific CTL generation was independent of the class II allotype, and mice depleted of CD4+ cells generated allospecific CTL, indicating independence of class II-CD4+ cell interactions and resulting CD4+ cell-secreted lymphokines. FACS staining with a variety of V beta-binding antibodies did not show a superantigen-like depletion or enrichment of any tested V beta + subset during infection. Several experiments provided evidence in support of direct stimulation of CD8+ cells via the T cell receptor: (a) both virus- and allo-specific killing were enriched within a given V beta subpopulation; (b) relative CTL precursor frequencies against different class I alloantigens changed during the course of virus infection; (c) the relative levels of virus-induced, allospecific CTL-mediated lysis at day 8 after infection did not parallel the CTL precursor frequencies before infection; and (d) limiting dilution analyses of day 8 LCMV-infected spleen cells stimulated by virus-infected syngeneic peritoneal exudate cells (PEC) revealed not only the expected virus-specific CTL clones, but also a high frequency of clones that were cross-reactive with allogeneic and virus-infected syngeneic targets. In addition to the virus cross-reactive allospecific CTL clones, virus-infected PEC also stimulated the generation of some allospecific clones that did not lyse virus-infected fibroblasts. Surprisingly, LCMV-infected PEC were much more efficient at stimulating allospecific CTL clones from day 8 LCMV-infected splenocytes than were allogeneic stimulators. These results indicate that at least part of the polyclonal allospecific CTL response elicited by acute virus infection is a consequence of the selective expansion of many clones of allospecific CTL which cross-react with virus-infected cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Behavioral momentum and Pavlovian conditioning
Authors: Randolph C. Grace, John A. Nevin
Journal: Behavioral and Brain Sciences (2004)

The constructs of behavioral mass in research on the momentum of operant behavior and associative strength in Pavlovian conditioning have some interesting parallels, as suggested by Savastano &amp; Miller . Some recent findings challenge the strict separation of operant and Pavlovian determiners of response rate and resistance to change in behavioral momentum, renewing the need for research on the interaction of processes that have traditionally been studied separately. Relatedly, Furedy notes that some autonomic responses may be refractory to conditioning, but a combination of operant contingencies and enriched Pavlovian stimulus-reinforcer relations may prove effective.
A mechanism of accumulation and activation of polymorphonuclear cells and macrophages in the liver of alcoholics; production of chemotactic factor by hepatocytes exposed to ethanol
Authors: Yasushi Shiratori, Hiroshi Takada, Kenji Hai, Hiroki Kiriyama, Mitsugu Tanaka, Yutaka Komatsu, Shuichiro Shina, Tateo Kawase, kazunori Matsumoto
Journal: Journal of Hepatology (1992)
Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer
Authors: G.V. Scagliotti, I. Bondarenko, F. Blackhall, F. Barlesi, T.-C. Hsia, J. Jassem, J. Milanowski, S. Popat, J.M. Sanchez-Torres, S. Novello, R.J. Benner, S. Green, K. Molpus, J.-C. Soria, F.A. Shepherd
Journal: Annals of Oncology (2014)