tbuckley/cabot-search huggingface dataset:
Abstract 4005: JAK/STAT activation following Src inhibition is mediated by the loss of SOCS2 expression
Authors: Banibrata Sen, Shaohua Peng, Faye M. Johnson
Journal: Cancer Research (2010)

Abstract Systemic therapy that results in both decreased invasion and significant cytotoxicity would be ideal to treat head and neck squamous cell carcinoma (HNSCC). One promising therapeutic target is Src due to its well-defined roles in both invasion and survival. STAT3 is a key mediator of the oncogenic effects of Src. However we previously found that sustained Src inhibition resulted in only transient inhibition of STAT3. Likewise, Src inhibition resulted in a universal reduction in invasion, but a more variable effect on apoptosis. Restoring STAT3 inhibition enhanced apoptosis. Previously we showed that STAT3 reactivation was mediated by JAK2 kinase activation and altered JAK2-STAT3 binding. Reactivation of JAK2/STAT3 suggests a feedback loop, possibly via the loss of a negative regulator. Of the three known feedback loops that regulate JAK/STAT function, we considered the most likely candidate to be the suppressors of cytokine signaling (SOCS) proteins, which can compete for STAT binding and inhibit JAK kinase activity. To determine if SOCS proteins are involved in JAK/STAT3 reactivation, we measured RNA levels of all 8 SOCS family members in 5 HNSCC cell lines using quantitative PCR. The expression of most of the SOCS decrease after initial Src inhibition, but recover, consistent with their regulation by STAT3. However, the expression of SOCS2 decreased in all 5 lines. Likewise, we found that the addition of a molar stoichiometric amount of recombinant SOCS2 inhibits Jak2 kinase activity in vitro. To confirm that SOCS2 regulates STAT3 activity, we knocked-down SOCS2 by siRNA which resulted in the activation of STAT3. Similarly, transient overexpression of SOCS2 resulted in significant downregulation of activated STAT3. Others have reported that STAT5 can regulate SOCS2 expression. Consistent with this, we found that Src inhibition led to durable STAT5 inhibition. Moreover, the depletion of both isoforms of STAT5 (a and b) with siRNA resulted in a dramatic downregulation of the SOCS2 expression. To determine the biological significance of SOCS2 expression, we discovered that specific SOCS2 depletion reduced HNSCC cytotoxicity following Src inhibition. Our results demonstrate that sustained Src inhibition leads to the loss of SOCS2 expression via STAT5 inhibition. The loss of SOCS2 allows the recovery of JAK2 kinase activity, JAK2/STAT3 binding, STAT3 activation, and cell survival despite durable Src inhibition. To our knowledge, this feedback pathway has never been described previously. Given that pharmacologic Src and JAK inhibitors are currently being evaluated in clinical trials, these results have significant implications for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4005.
NHS trust boards must declare members' interests
Authors: L Beecham
Journal: BMJ (1994)

NHS trust boards will have to keep a register of directors' and members' interests under new codes of conduct and accountability published last week, and these registers will be available to the public. The secretary of state for health published draft codes for consultation in January (22 January, p 225) and has received over 400 responses. Mrs Bottomley believes that the new codes will strengthen the trusts' accountability to her and to the public. When they are appointed all board members will have to subscribe to the codes. “We are determined,” she said, “to reaffirm that the pursuit of private gain plays no part in the decision making of NHS board members.”

The main features of the codes are clearer definitions of the functions of chairpeople and non-executive board members, who will have to declare any private interests which are “material and relevant to NHS business.” Boards will have to establish audit and remuneration and terms of service committees. They will have to spell out clearly which of their committees may hold delegated functions. The NHS Executive will clarify the position on all financial constraints which apply to NHS authorities and trusts. The boards' annual reports will have to set out the total remuneration from the trust of the chairman and executive and non-executive board members.

The codes will also put an obligation on health authorities to publish an annual report on their performance and stewardship of public finances - an annual report is already mandatory for NHS trusts.

The average allocation to general practitioner fundholders per patient is …
BK antibody and virus-specific IgM responses in renal transplant recipients, patients with malignant disease, and healthy people.
Authors: A J Flower, J E Banatvala, I L Chrystie
Journal: BMJ (1977)

Haemagglutination-inhibition (HAI) antibodies to BK virus, including BK-virus-specific IgM, were determined before and after renal transplantation in 20 patients, in 57 patients with malignant disease, and in 66 healthy controls, Before transplantation 11 of the renal transplant recipients were seronegative, but eight later serocconverted, two before and six after transplantation. Twenty of the patients with malignant disease and 22 controls were also seronegative. The geometric mean titre of BK HAI antibodies was significantly higher among transplanted patients (1/180) than among controls (1/90). BK-virus-specific IgM antibody was detected in seven renal transplant recipients, six patients with malignant disease, and 13 healthy controls. In transplant recipients BK-virus-specific IgM antibody usually persisted throughout the duration of the study, and studies on controls from whom second serum samples were available suggested that they too had persistent BK-virus-specific IgM responses. The geometric mean titre of BK-virus-specific IgM HAI antibody was significantly greater in post-transplantation sera (1/223) than in control sera (1/28). The specificity of the detection of BK-virus-specific IgM HAI antibody was confirmed by direct visualisation of antibody by immune electron microscopy. The persistence of BK-virus-specific IgM suggested that BK virus continued to provide an antigenic stimulus. Nevertheless, there was no obvious association between the serological findings and any clinical features, and prospective studies will be needed to elucidate any such association.
Integrative Analysis of Head and Neck Cancer Identifies Two Biologically Distinct HPV and Three Non-HPV Subtypes
Authors: Michaela K. Keck, Zhixiang Zuo, Arun Khattri, Thomas P. Stricker, Christopher D. Brown, Matin Imanguli, Damian Rieke, Katharina Endhardt, Petra Fang, Johannes Brägelmann, Rebecca DeBoer, Mohamed El-Dinali, Serdal Aktolga, Zhengdeng Lei, Patrick Tan, Steve G. Rozen, Ravi Salgia, Ralph R. Weichselbaum, Mark W. Lingen, Michael D. Story, K. Kian Ang, Ezra E.W. Cohen, Kevin P. White, Everett E. Vokes, Tanguy Y. Seiwert
Journal: Clinical Cancer Research (2014)

Current classification of head and neck squamous cell carcinomas (HNSCC) based on anatomic site and stage fails to capture biologic heterogeneity or adequately inform treatment.Here, we use gene expression-based consensus clustering, copy number profiling, and human papillomavirus (HPV) status on a clinically homogenous cohort of 134 locoregionally advanced HNSCCs with 44% HPV(+) tumors together with additional cohorts, which in total comprise 938 tumors, to identify HNSCC subtypes and discover several subtype-specific, translationally relevant characteristics.We identified five subtypes of HNSCC, including two biologically distinct HPV subtypes. One HPV(+) and one HPV(-) subtype show a prominent immune and mesenchymal phenotype. Prominent tumor infiltration with CD8(+) lymphocytes characterizes this inflamed/mesenchymal subtype, independent of HPV status. Compared with other subtypes, the two HPV subtypes show low expression and no copy number events for EGFR/HER ligands. In contrast, the basal subtype is uniquely characterized by a prominent EGFR/HER signaling phenotype, negative HPV-status, as well as strong hypoxic differentiation not seen in other subtypes.Our five-subtype classification provides a comprehensive overview of HPV(+) as well as HPV(-) HNSCC biology with significant translational implications for biomarker development and personalized care for patients with HNSCC.
Nicotine Patches: Up in Smoke?
Authors: Mark Jameson
Journal: JAMA (1992)

To the Editor.  —Cigarette smoking is a well-identified risk factor for heart disease and lung cancer, and cessation of smoking results in a decline of risk. 1 Smoking has also been identified by the Surgeon General as the No. 1 public health problem. Despite their importance, smoking cessation programs have generally not been popular with physicians because of the time involved, low success rate, and nonreimbursement. The recent introduction of nicotine patches is a watershed event in treating nicotine addiction. The patches are so popular with the public that the drug manufacturers cannot keep up with the demand. 2 The 1-year success rates of 29% to 35% 3 compare favorably with success rates for treatment of certain cancers and other chronic diseases.  Few insurance companies will reimburse for the nicotine patches, and some of those are discontinuing their coverage. 2 Instead, the insurance carriers continue to prefer to pay the
(Ca<sup>2+</sup>+Mg<sup>2+</sup>)‐ATPase activity of sickle cell membranes: Decreased activation by red blood cell cytoplasmic activator
Authors: Rama M. Gopinath, Frank F. Vincenzi
Journal: American Journal of Hematology (1979)

Abstract Human red blood cells (RBCs) contain a cytoplasmic protein that activates membrane‐bound (Ca 2+ + Mg 2+ )‐ATPase and the transport of Ca 2+ . The (Ca 2+ + Mg 2+ )‐ATPase of sickle cells showed a less than normal response to this activator. This was true whether the activator was obtained from normal or sickle cells. Activator present in sickle cell hemolysates fully activated the (Ca 2+ + Mg 2+ )‐ATPase of normal RBC membranes. These results demonstrate that membranes of sickle cells are defective in their response to the activator. Neither the apparent affinity for calcium nor the apparent affinity for activator was different comparing the (Ca 2+ + Mg 2+ )‐ATPase of sickle and normal membranes. Young, mature, and irreversibly sickled cells were separated by density gradient centrifugation, and membranes were prepared from each of these cell populations. No significant differences in ATPase activities were found based on cell age (density). The (Ca 2+ + Mg 2+ )‐ATPase of all populations of sickle cells showed a decreased response to the activator. Thus, it appears unlikely that the decreased response of the (Ca 2+ + Mg 2+ )‐ATPase of sickle cells is due to membrane damage caused by repeated sickling during the life‐span of the cell. Reduced activation of (Ca 2+ + Mg 2+ )‐ATPase by the cytoplasmic activator may account for calcium accumulation in sickle cells.
Abstract 4277: Prosective cloning of highly invasive differentiated breast cancer cells
Authors: Jiyoung Kim, René Villadsen, Louise Fogh, Agla J. Fridriksdottir, Fritz Rank, Vera Timmermans-Wielenga, Lone Rønnov-Jessen, Mina J. Bissell, Ole W. Petersen
Journal: Cancer Research (2010)

Abstract Breast cancer consists of a variety of cell types with distinct phenotypes. Here, we examine the heterogeneity by a panel of normal human breast lineage markers from a recently described hierarchy. By use of multicolor imaging, we show that random heterogeneity is in fact patterned. Tumor cells exhibit traits of normal luminal-, and basal- progenitors, respectively. By combining fluorescence activated cell sorting and single cell cloning, we demonstrate that the patterned heterogeneity reflects a lineage hierarchy reminiscent of that seen in the normal breast. Distinct classes of tumor cells have differing functional abilities and behavior. Thus, multipotent basal-like tumor cells with stem cell properties give rise to lineage restricted tumor cells with luminal-like properties. Luminal-like tumor cells, in turn, are most aggressive as revealed by soft agar colony formation, invasiveness, and in vivo tumorigenecity. We therefore conclude that breast cancer heterogeneity, to some extend, arise as a consequence of normal-like lineage evolution. However, more importantly, the progeny of cancer stem cells remains deregulated raising serious doubts about the current concept of the cancer stem cell as the ultimate drug target. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4277.
Gaining a foothold: tackling poverty, gender inequality, and HIV in Africa
Authors: Julia C Kim, Charlotte H Watts
Journal: BMJ (2005)

<h3>Aim</h3> To explore the acceptability and feasibility of a parental early warning tool, called the Congenital Heart Assessment Tool (CHAT), for parents going home with their infant between first and second stage of surgery for complex congenital heart disease. <h3>Background</h3> Home monitoring programmes were developed to aid early recognition of deterioration in fragile infants between first and second surgical stage. However, this necessitates good discharge preparation to enable parents to develop appropriate knowledge and understanding of signs of deterioration to look for and who to contact. <h3>Design</h3> This was a longitudinal qualitative feasibility study, within a constructivist paradigm. Parents were taught how to use the CHAT before taking their infant home and asked to participate in semistructured interviews at four time points: before discharge (T0), 2 weeks after discharge (T1), 8 weeks after discharge (T2) and after stage 2 surgery (T3). Interviews were transcribed verbatim and thematically analysed. <h3>Setting</h3> One tertiary children’s cardiac centre in the UK. <h3>Subjects</h3> Twelve parents of eight infants who were discharged following first stage cardiac surgery for complex congenital heart disease, between August 2013 and February 2015. <h3>Results</h3> Four main themes emerged: (1) parental preparation and vigilance, (2) usability, (3) mastery, and (4) reassurance and support. <h3>Conclusions</h3> The study highlighted the benefit of appropriately preparing parents before discharge, using the CHAT, to enable identification of normal infant behaviour and to detect signs of clinical deterioration. The study also demonstrated the importance of providing parents with information about when and who to call for management advice and support.
Cardiorespiratory responses of cardiac transplant patients to graded, symptom-limited exercise.
Authors: W M Savin, W L Haskell, J S Schroeder, E B Stinson
Journal: Circulation (1980)

The electrocardiographic and ventilatory responses of 15 denervated heart patients who had undergone cardiac transplantation and 14 age-matched, normally innervated men were compared to assess the pattern of response to graded treadmill exercise. A 5-minute postexercise venous lactate sample was also obtained. Respiratory exchange ratio and ventilation (Ve) were higher in denervated patients than in normals during submaximal exercise. Peak values (normals vs denervated) for heart rate (172 vs 159 beats/min), blood pressure (189 vs 167 mm Hg), oxygen uptake (37 vs 25 ml/kg/min), oxygen pulse (0.22 vs 0.16 ml/kg/beat) and work time (26.2 vs 18.0 minutes) were higher in normals than in cardiac transplant recipients. Peak ventilatory equivalent (2.14 vs 3.13 l/ml/kg) and lactate values were higher for transplants than for normal subjects, but there were no significant intergroup differences in peak Ve or in the respiratory exchange ratio. In cardiac transplant recipients, work time correlated inversely with a measure of rejection history (r = -0.59, p less than 0.01). The response of cardiac transplant recipients to treadmill work differs from that of normal men and reflects a diminished ability to meet the oxygen demands of the exercising periphery.
The One-Year Clause in Reciprocity.
Authors: E. L. B. Godfrey
Journal: JAMA (1907)

Camden, N. J., Dec. 21, 1906. <h3>To the Editor:</h3> —The communication inThe Journal, December 15, from Dr. George W. Webster, president of the Illinois State Board of Health, concerning the requirement that an applicant for the endorsement of a state medical license should have held the same for at least one year prior to its indorsement by a reciprocity state, is worthy of notice, both because Dr. Webster requests the<i>pros</i>and<i>cons</i>of the question and because of its interest to the profession. Dr. Webster states that after Jan. 1, 1907, the Illinois State Board of Health will not reciprocate with any state exacting this requirement. In this respect the Illinois State Board of Health has taken a proper stand. When a medical licentiate of a state presents his original state license, earned on examination, with due certification thereto, and can substantially meet in all other respects the
Panic Attacks in the Community
Authors: Gerald L. Klerman
Journal: JAMA (1991)

This article focuses on social morbidity and health care utilization in persons with panic attacks not meeting full diagnostic criteria for panic disorder. The findings are based on data from a random sample of over 18,000 adults drawn from five US communities. Panic attacks not meeting full criteria for panic disorder have a relatively high lifetime prevalence (3.6% of the adult population). Persons with panic attacks had impairment in perceived physical and emotional health, and in occupational and financial functioning, increased use of health care facilities, emergency departments, and psychoactive drugs. Persons with panic attacks were intermediate in severity between those with panic disorder and those with other psychiatric disorders. The findings could not be explained by comorbidity with other psychiatric disorders. We conclude that panic attacks have clinical significance and are associated with substantial morbidity.
Overexpression of Sonic Hedgehog in the Lung Mimics the Effect of Lung Injury and Compensatory Lung Growth on Pulmonary Sca-1 and CD34 Positive Cells
Authors: Anja Krause, Yaqin Xu, Ju Joh, Ralf Hubner, Austen Gess, Thomas Ilic, Stefan Worgall
Journal: Molecular Therapy (2009)

Cells localized in the bronchioalveolar duct junction of the murine lung have been identified as potential bronchioalveolar stem cells. Based on the surface marker expression, two main phenotypes have been proposed: Sca-1(+), CD34(+), CD45(-), Pecam(-) and Sca-1(low), CD34(-) CD45(-), Pecam(-) cells. An increase in the number of Sca-1(+), CD34(+) CD45(-), Pecam(-) cells and activation of the sonic hedgehog (Shh) pathway was observed following unilateral pneumonectomy and naphthalene-induced airway injury. Overexpression of Shh in the respiratory tract also resulted in an increase of this cell population. Syngeneic transplantation of beta-galactosidase-expressing bone marrow cells demonstrated that the increase of Sca-1(+), CD34(+), CD45(-), Pecam(-) cells in the lung was a result of local proliferation. Intratracheal administration of purified Shh-stimulated Sca-1(+), CD45(-), Pecam(-) cells coexpressing CD34 to syngeneic mice following pneumonectomy resulted in engraftment of these cells predominantly in the airways for up to 3 months, whereas Sca-1(-), CD45(-), Pecam(-) cells did not engraft. This study suggests that local Sca-1(+), CD34(+), CD45(-), Pecam(-) cells are stimulated during compensatory lung growth, following airway injury and overexpression of Shh and have some potential to engraft in the airways, without showing clonal properties in vivo.
Acute Kidney Injury and Chronic Kidney Disease as Interconnected Syndromes
Authors: Lakhmir S. Chawla, Paul W. Eggers, Robert A. Star, Paul L. Kimmel
Journal: New England Journal of Medicine (2014)

This review considers evidence that acute and chronic kidney diseases are not distinct entities but rather are closely interconnected. The implications of this insight are discussed in terms of the approach to patients with kidney disease.
Severe digital necrosis in an elderly patient with heterozygous factor V Leiden mutation
Authors: G.K. Patel, E. Morris, M.R. Rashid, A.V. Anstey
Journal: British Journal of Dermatology (2000)

We report an 81‐year‐old female with a heterozygous factor V Leiden mutation who developed purpura fulminans. Digital necrosis, a characteristic clinical feature of purpura fulminans was prominent. Purpura fulminans is more common in children and adult cases are rare. Of eight reported cases of purpura fulminans resulting from a heterozygous factor V Leiden mutation recorded in the literature, only two were in adults: 40 and 42 years of age, respectively. This is the first report of this condition arising in a patient in her eighties.
Cardiovascular dynamics in women during the menstrual cycle and oral contraceptive therapy
Authors: W. A. Littler, R. Bojorges-Bueno, J. Banks
Journal: Thorax (1974)

<b>Littler, W. A., Bojorges-Bueno, R., and Banks, Judy (1974).</b><i>Thorax</i>, <b>29</b>, 567-570. <b>Cardiovascular dynamics in women during the menstrual cycle and oral contraceptive therapy.</b> Measurements of pulmonary blood flow and cardiac output have been made in 31 healthy women during the follicular and luteal phases of their menstrual cycle using nitrous oxide whole body plethysmography. The women were divided into three groups: 12 women were receiving oestrogen-progestogen contraceptive pills, 8 were receiving progestogen-only pills, and 11 were using either alternative methods of contraception or none at all. There was no significant difference in the values of cardiac index, pulmonary arterial distensibility, heart rate or systemic blood pressure during the two phases of the menstrual cycle in any of the three groups. When the three groups were compared the cardiac output showed the most significant difference, being greatest in the oestrogen-progestogen group, the progestogen-only group occupying an intermediate position. An increased cardiac output might play a part in the development of systemic hypertension in some women receiving oral contraceptives and could also add a risk to women with pre-existing heart disease.
Multiple Brown Tumors Simulating Bone Metastases
Authors: MELTEM CAGLAR, SENIHA NALDÖKEN
Journal: Clinical Nuclear Medicine (2000)

A 55-year-old man with multiple brown tumors who initially was thought to have multiple bone metastases is described. He had elevated parathyroid hormone levels and was referred to the nuclear medicine department, where a parathyroid adenoma was diagnosed. At surgery, abnormal lymph nodes were seen, which were found to contain metastatic thyroid papillary carcinoma cells. On further exploration, the patient’s bone scintigraph revealed multiple sites of increased uptake but no bone abnormalities on whole-body iodine and Tc-99m MIBI scans.