tbuckley/cabot-search huggingface dataset:
Targeting Heat Shock Response to Sensitize Cancer Cells to Proteasome and Hsp90 Inhibitors
Authors: Nava Zaarur, Vladimir L. Gabai, John A. Porco, Stuart Calderwood, Michael Y. Sherman
Journal: Cancer Research (2006)

Abstract Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment. (Cancer Res 2006; 66(3): 1783-91)
Long-Term Follow Up of a "Sporadic" Unilateral Pheochromocytoma Revealing Multiple Endocrine Neoplasia MEN2A-2 in an Elderly Woman
Authors: Andreas Weinhäusel, Annemarie Behmel, Bruce A. J. Ponder, Oskar A. Haas, Bruno Niederle, Alois Gessl, Heinrich Vierhapper, Roswitha Pfragner
Journal: Endocrine Pathology (2003)
Informed consent
Authors: Peter D Singleton
Journal: BMJ (2005)

Endovascular repair is not worse than open repair of abdominal aortic aneurysmsEditor-The title and interpretation of the EVAR trial results in the POEM are misleading and incorrect. 1Mortality figures were quoted both as aneurysm related and all cause deaths.The 30 day mortality was 1.7% in the EVAR group, which is significantly lower than 4.7% in the open repair group.Surprisingly, the POEM somehow interpreted 30 day mortality to be less than 1% for both groups, which is clearly an error.The confidence intervals (odds ratio 0.35, 95% confidence interval 0.16 to 0.77, P = 0.009) make type I error unlikely.If preintervention deaths are added to the figures 30 day mortality was calculated at 3.5% for endovascular repair and 7.1% for open surgery. 2 The advantage of endovascular repair is sustained at four years, with 4% aneurysm related deaths in the EVAR group compared with 7% in the open repair group.This confers a 3% absolute reduction in aneurysm related mortality.The all cause mortality rate was comparable in both groups at four years.Endovascular repair offers a 30 day lower risk treatment compared with open surgery in patients who are medically fit with an abdominal aortic aneurysm.Compared with open repair, endovascular repair offers no advantage with respect to all cause mortality and health related quality of life; and is more expensive; however, it confers a 3% improved aneurysm related survival which persists at four years.The POEM's message that endovascular repair is worse than open repair is inaccurate and not evidence based.
Consultant Appointments and Medical Representation
Authors: I. M. Librach
Journal: BMJ (1966)

falcipariem parasites were found in the blood after 19 months' stay away from a malarious zone.It is interesting to note that the patient in Walters's report was also five months pregnant.McGregor and Smith2 found that primigravidae seemed to lose immunity against P. falciparum, and Bruce- Chwatt3 observed an increased parasite density during parturition.These two cases tend to support the suggestion that pregnancy might predispose to clinical recrudescence of P. falciparuni malaria.In view of the com- plications associated with this infection great vigilance in detecting and treating it during the antenatal period is necessary.
T- and B cell clones circulate between synovial tissue and lymph node in early stages of rheumatoid arthritis (RA): elucidating the role of lymph nodes in RA
Authors: P. L. Klarenbeek, M. J. de Hair, M. E. Doorenspleet, S. Alivernini, B. D. C. van Schaik, M. G. van de Sande, F. H. Berger, A. H. C. van Kampen, D. M. Gerlag, F. Baas, P. P. Tak, N. de Vries
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> T- and B cell receptor (TCR, BCR) mediated responses are likely to play an important role in the initiation of rheumatoid arthritis (RA). The authors recently presented a new high-throughput protocol that can be used to find and quantify T- and B cell expansions. Previous observations from their group suggested that sites other than the synovial tissue (ST) might be involved in the earliest phases of the disease. Therefore, the authors examined the TCR and BCR repertoire in the lymph nodes (LNs) of early RA patients. <h3>Objective</h3> To characterise the TCR and BCR repertoire in LN and ST, and investigate overlap in clones between these sites. <h3>Methods</h3> mRNA was isolated from paired LN, ST and peripheral blood (PB) samples of 2 disease-modifying antirheumatic drug-naive anti-cyclic citrullinated peptide antibody positiveRA-patients after arthroscopic ST sampling of an inflamed ankle joint and biopsy sampling of a regional LN. The disease duration in both patients was &lt;1 year. TCRs (for both pts) and BCRs (for 1 pt) were (linearly) amplified using primers for all V(ariable genes) of the TCR-β-chain and BCR-heavy-chain. The samples were processed using a Genome Sequencer (454). The frequency of each clone was determined by its CDR3-frequency (% of total). Clones &gt;0.5% were arbitrarily considered as highly expanded clones (HECs). <h3>Results</h3> The LN samples showed &gt;1000 B- and T cell clones, but only few HECs were detected (average 8 (T cells) and 25 (B cells), respectively). The ST-samples showed strikingly more T cell HECs (41), but a comparable number of B cell HECs (15). The HECs reached frequencies of up to 20% (T cells) and 7% (B cells) in LN compared to 14% and 36%, respectively, in ST. The HECs were far more dominant in ST where the cumulative frequency of the HECs was 82% (T cells) and 57% (B cells) of the analysed cells while this was only 16% and 35% in LN. HECs were generally not shared between LN, ST and PB, but there was clear evidence of circulation. 25% of the ST T cell-HECs were also detected in LN (as low frequency clones), while this was 40% for ST B cell-HECs. <h3>Conclusions</h3> HECs (T- and B cell) can be detected in both ST and LN of RA-patients. Up to 40% of the ST HECs are also found as low frequency clones in LN. These results may be explained by circulation of clones between ST and LN.
Triple Retinal Infection with Human Immunodeficiency Virus Type 1, Cytomegalovirus, and Herpes Simplex Virus Type 1
Authors: Volker Rummelt, Carmen Rummelt, Gerhard Jahn, Hartmut Wenkell, Christian Sinzger, Ursula M. Mayer, Gottfried O.H. Naumann
Journal: Ophthalmology (1994)
Variations in Mortality and Length of Stay in Intensive Care Units
Authors: William A. Knaus
Journal: Annals of Internal Medicine (1993)

Objective: To evaluate the amount of variation in in-hospital mortality and length of intensive care unit (ICU) stay that can be accounted for by clinical data available at ICU admission. Design: Inception cohort study. Setting: Forty-two ICUs in 40 hospitals, including 26 hospitals that were randomly selected and 14 large tertiary care hospitals that volunteered for the study. Participants: A consecutive sample of 16 622 patients and 17 440 ICU admissions. Measurements and Main Outcomes: Data on selected demographic characteristics, comorbidity, and specific physiologic variables were recorded during the first ICU day for an average of 415 admissions at each ICU; hospital discharge status (dead or alive) and length of ICU stay were recorded for individual patients; and the ratio of actual to predicted in-hospital mortality, standardized mortality ratios, and the ratio of actual to predicted length of ICU stay were recorded for individual ICUs. Results: Unadjusted in-hospital mortality rates for the 42 units varied from 6.4% to 40%, and 90% (R2 = 0.90) of this variation was attributable to patient characteristics at admission. The standard mortality ratio varied from 0.67 to 1.25. The mean unadjusted length of ICU stay varied from 3.3 to 7.3 days, and 78% of the variation (R2 = 0.78) was attributed to patient and selected institutional characteristics. The best performing unit had a length of stay ratio of 0.88, whereas the poorest performing unit had a ratio of 1.21. Conclusions: Clinicians can use readily available admission data to adjust for considerable variations in patient severity and type in different ICUs. Such data should permit precise evaluation and comparison of ICU effectiveness and efficiency, which varied substantially in this study, and result in improved methods of risk prediction and evaluation of new medical practices.
PHASE II TRIAL OF 131*** CC49 PLUS ALPHA INTERFERON (***FN α) IN REFRACTORY METASTATIC BREAST CANCER
Authors: D. A. Podoloff, L. P. Kasl, V. A. Bhadkamkar, D. J. Macey, M. G. Rosenblum, E. J. Grant, H. Z. Zhang, R. L. Katz, P. T. Rolger, D. LeBherz, M. S. South, D. J. Booser, K. Dhingra, J. W. Greiner, J. Schlom, J. L. Murray
Journal: Clinical Nuclear Medicine (1994)

Podoloff, D. A.; Kasl, L. P.; Bhadkamkar, V. A.; Macey, D. J.; Rosenblum, M. G.; Grant, E. J.; Zhang, H. Z.; Katz, R. L.; Rolger, P. T.; LeBherz, D.; South, M. S.; Booser, D. J.; Dhingra, K.; Greiner, J. W.; Schlom, J.*; Murray, J. L. Author Information
A CASE OF RETROPHARYNGEAL FIBROMA
Authors: N. B. Odgers
Journal: BMJ (1907)

must be shown that the micro-organism can by suitable methods be obtained from a long series of cases, which must be chosen with dae regard to their acuteness and their freedom from suspicion of complications; and secondly, it must be clearly demonstrated that the organism itself is a distinct and definite variety of streptococcus.
ASTHMA FROM THE STANDPOINT OF THE RHINOLOGIST
Authors: EDWIN McGINNIS
Journal: JAMA (1927)

It is of historical interest that the Egyptians, Greeks and Romans recognized asthma, and that it represented as much of a problem in their time as it does at present. Salter's explanation in 1864 of this age-old problem was that asthma was essentially, with perhaps the exception of a single class of cases, exclusively a nervous disease. In 1878 J. R. Berkart stated that "asthma was a symptom of chronic bronchitis and emphysema, as well as one of those that are present in various cardiac affections." He compiled a textbook, which appeared in 1911, in which he made the statement that "asthma is a symptom of fibrinous bronchitis and is caused by a micro-organism." F. H. Bosworth, as a rhinologist, looked on asthma as a vasomotor rhinitis, depending on three prerequisites: first, a neurotic temperament, according to the teachings of Salter; second, pathologic conditions in the mucosa of the nasal
Novel epitope begets a novel pathway in type 1 diabetes progression
Authors: Jeffrey A. Frelinger
Journal: Journal of Clinical Investigation (2008)

While CD8+ T cells are critical to diabetogenesis in NOD mice, evidence of their involvement in human type 1 diabetes (T1D) has been circumstantial. The existence of CD8+ T cells specific for β cell peptides has been demonstrated, but functional data regarding the role of these cells in T1D have been lacking. In this issue of the JCI, Skowera et al. describe an unusual self-peptide epitope derived from the leader sequence of preproinsulin (PPI) and show that 50% of HLA-A2+ patients with new-onset T1D possessed circulating CD8+ T cells specific for this epitope, suggesting that PPI plays a critical role in the development of T1D (see the related article beginning on page 3390). They also report that β cells upregulate PPI expression in the presence of high glucose levels, rendering these cells more susceptible to lysis and potentially accelerating disease. This suggests that interventions aimed at decreasing the PPI-specific CD8+ T cell response early after T1D diagnosis may be efficacious in ameliorating the disease process.
Exercise training prevents β‐adrenergic hyperactivity‐induced myocardial hypertrophy and lesions
Authors: Andrey J. Serra, Maria L. Higuchi, Silvia S.M. Ihara, Ednei L. Antônio, Marília H.H. Santos, Maria T.N.M. Bombig, Paulo J.F. Tucci
Journal: European Journal of Heart Failure (2008)
Commentary: Evidence based information for women is important
Authors: M. Newburn, M. Gready
Journal: BMJ (1996)

The “Informed Choice” leaflets produced by the Midwives' Information and Resource Service and the NHS Centre for Reviews and Dissemination are of fundamental importance. They set out to provide users of the health service—in this case pregnant women—with the best evidence available on the effectiveness of different aspects of maternity care, in an accessible format and language. Significantly, the leaflets encourage women to ask questions about what procedures are for and why they are needed.

The case study by S Oliver and colleagues is important because it examines how the leaflet on ultrasound screening was received and responded to by women, ultrasonographers, and midwives. We need to know how research evidence is greeted and how it …
Evaluation of a computerised polysomnography system.
Authors: H Biernacka, N J Douglas
Journal: Thorax (1993)

BACKGROUND: Manual analysis of sleep, breathing, and oxygenation records is the "gold standard" for diagnosing sleep abnormalities but is time consuming and cumbersome. The accuracy and cost of a computerised sleep analysis system have therefore been investigated. METHODS: Manual and computerised (CNS Sleep Lab) scores from 43 consecutive clinical sleep studies were prospectively compared for accuracy and the time and costs were recorded. RESULTS: There were good correlations and no systematic differences between manual and computer scoring for total sleep time, sleep onset latency, and duration of REM sleep. There was a small but clinically insignificant systematic difference in breathing pattern analysis, the number of hypopnoeas/hour being lower with manual than with computer scoring (13 (SE 3) v 15 (SE 3)/hour). There was no difference between computer and manual scoring of the frequency of apnoeas, so the frequency of apnoeas + hypopnoeas was clinically insignificantly higher with computer scoring with a highly significant correlation between the two techniques. The time taken to perform the analyses was not different between the two methods (manual 83 (SE 8) v computer 86 (SE 8) minutes). The computer system was six times more expensive than the manual system and annual running costs, including full maintenance contract and 15% depreciation, were twice as great. CONCLUSION: The CNS Sleep Lab is sufficiently accurate for use in clinical sleep studies but is significantly more expensive and does not save technician time.
Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.
Authors: D J Dusser, T D Djokic, D B Borson, J A Nadel
Journal: Journal of Clinical Investigation (1989)

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyper-responsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.
Pathways of intracellular trafficking and release of ferritin by the liver in vivo: The effect of chloroquine and cytochalasin D
Authors: Grant A. Ramm, Lawrie W. Powell, June W. Halliday
Journal: Hepatology (1994)

We have previously shown that the clearance of exogenous ferritin and the release of endogenous ferritin into both serum and bile are altered by the microtubular inhibitor colchicine. In this study we further examined the role of the lysosome-endosome pathway in ferritin metabolism. We examined the effect of the lysosomotropic agent chloroquine and the microtubular inhibitor cytochalasin D on the uptake and release of ferritin by normal and iron-loaded rats under basal conditions and in the presence of an exogenous tissue ferritin load. Either chloroquine (50 mg/kg body wt) or cytochalasin D (0.9 microgram/100 gm body wt/min) was administered to normal and iron-loaded rats at zero time. Rats were also infused with either saline solution or rat liver ferritin containing a trace amount of 125I-ferritin. The clearance of 125I-ferritin from the circulation was not affected by chloroquine or cytochalasin D either in normal or in iron-loaded rats; however, both chloroquine and cytochalasin D decreased the serum ferritin concentration in normal rats to 39% +/- 9% and 22% +/- 7% of the baseline serum ferritin levels, respectively, implying that both drugs inhibited the release of endogenous ferritin in normal rats. In iron-loaded rats both chloroquine and cytochalasin D decreased the biliary ferritin concentration to 11% +/- 1% and 37% +/- 4% of the baseline ferritin levels, respectively, and the 125I protein-bound counts per minute in the bile to 50% of the control result. This finding is consistent with an inhibitory effect of both drugs on the biliary excretion of endogenous ferritin and the intracellular transport of exogenous ferritin, respectively. In the presence of an exogenous tissue ferritin load, there was no detectable inhibitory effect of either drug on the biliary excretion of either endogenous or exogenous ferritin. These results provide the following evidence: (a) the receptor-mediated endocytosis of ferritin is not dependent on functioning lysosomes or microfilaments; (b) the release of endogenous ferritin into the serum of normal rats and the bile of iron-loaded rats is a chloroquine-sensitive, microfilament-dependent process; (c) the biliary excretion of trace amounts of exogenous ferritin is dependent on both chloroquine-sensitive vesicles and microfilaments; and (d) increased levels of exogenous ferritin are excreted directly into the bile by way of a second microfilament-independent, chloroquine-insensitive pathway. This study provides support for a physiological mechanism for the release of ferritin from the liver.
"Bolus" injections of lidocaine
Authors: E. K. Zsigmond
Journal: JAMA (1983)

<h3>To the Editor.—</h3> In "Fatal Occupational Injuries" (1982;248:692), Baker et al analyzed deaths related to work injuries during 1978 in Maryland. Of the 148 deaths, 25% involved road vehicles, 16% involved nonroad vehicles, 11% involved boats, and 5% involved aircraft. Firearms accounted for another 11% of injuries. A similar fatal injury pattern was seen in Oregon during 1980 and 1981, when there were 163 occupational fatalities. Here, deaths occurred as follows: 28.2%, traffic accidents; 4.3%, industrial vehicles; 7.4%, aircraft accidents; and 2.4%, homicides. It is surprising that fatal truck accidents are not more frequent. In Oregon, during 1980, about half of all trucks inspected by the State Police failed to pass routine safety inspections. Many of these vehicles lacked adequate brakes and posed a serious hazard to their drivers. They also represented a danger to the general public because of some of the hazardous cargos carried. This underscores the point
The natural history of actinic keratosis: a systematic review
Authors: R.N. Werner, A. Sammain, R. Erdmann, V. Hartmann, E. Stockfleth, A. Nast
Journal: British Journal of Dermatology (2013)

Knowledge about the development of untreated actinic keratosis (AK) and risk of progression into squamous cell carcinoma (SCC) is important. Therefore, we set out to synthesize primary data on the natural history of AK. We carried out a systematic literature search (Medline, Medline in Process, Embase, Cochrane) of studies on the natural course of AK, regarding (i) progression and regression rates per lesion-year, (ii) changes in total lesion counts over time, and (iii) spontaneous field regression and recurrence rates, taking into account studies on participants without immunosuppression and history of skin cancer, immunosuppressed patients and participants with a history of skin cancer and sunscreen use. Twenty-four eligible studies were identified providing data on at least one of the outcomes. Progression rates of AK to SCC ranged from 0% to 0·075% per lesion-year, with a risk of up to 0·53% per lesion in patients with prior history of nonmelanoma skin cancer. Rates of regression of single lesions ranged between 15% and 63% after 1 year. The data available on recurrence rates of single lesions 1 year after regression indicate a recurrence rate of 15-53%. Data on the relative change of total AK count over time are heterogeneous, and range from -53% to +99·1%. Spontaneous complete field regression rates range from 0% to 21%, with recurrences in 57%. In general, the available data are limited. Important methodological limitations apply. Currently, no reliable estimates concerning the frequency of AK developing into invasive carcinoma can be given, and further studies are needed.