tbuckley/cabot-search huggingface dataset:
Regulation of sarcolemmal Na+/H+ exchange by hydrogen peroxide in adult rat ventricular myocytes
Authors: A Snabaitis
Journal: Cardiovascular Research (2002)

Objective: To characterise the effects of exogenous H2O2 on sarcolemmal Na+/H+ exchanger (NHE) activity and determine the roles of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC) in observed effects. Methods: Sarcolemmal H+ efflux rate (JH) was determined by microepifluorescence at a pHi of 6.70 in adult rat ventricular myocytes, after two consecutive acid pulses in HCO3−-free medium; before the second pulse, cells (n=7–10/group) were exposed to H2O2 or vehicle and the change in JH (ΔJH) was used to quantify the change in NHE activity. ERK and p38 MAPK activities were determined by immunoblotting with phosphospecific antibodies. Results: Relative to control, ΔJH was increased by a 10-min exposure to 100, but not 1 or 10 μM H2O2 (1000 μM was not tolerated); 3 or 6 min exposure to 100 μM H2O2 was without effect. ERK and p38 MAPK activities were both increased by 100 μM H2O2 (peak at 6 min); the ERK kinase inhibitor PD98059 (10 μM), but not the p38 MAPK inhibitor SB203580 (1 μM), inhibited the H2O2-induced increase in ΔJH. H2O2-induced ERK activation was inhibited not only by PD98059 (10 μM), but also by the non-selective tyrosine kinase inhibitor genistein (3–100 μM), the EGF receptor kinase inhibitor AG1478 (3–300 nM) and the Src family kinase inhibitor PP2 (0.1–10 μM). The PKC inhibitors GF109203X (0.3–10 μM) and chelerythrine (1–30 μM) were without effect on ERK activation, although the former abolished the H2O2-induced increase in ΔJH. Conclusions: Our data demonstrate that, in adult rat ventricular myocytes, (i) hydrogen peroxide stimulates sarcolemmal NHE activity, (ii) this response requires activation of ERK and PKC, but not p38 MAPK, (iii) ERK activation occurs through tyrosine kinase-mediated, but PKC-independent, mechanisms
Use and Misuse of Waterfall Plots
Authors: Tiffany Shao, Lisa Wang, Arnoud J. Templeton, Raymond Jang, Francisco W. Vera-Badillo, Mairead G. McNamara, Myles Margolis, Tae Kyoung Kim, Mehrdad Sinaei, Hassan Shoushtari, Ian F. Tannock
Journal: JNCI Journal of the National Cancer Institute (2014)

“Waterfall plots” are used to describe changes in tumor size observed in clinical studies. Here we assess criteria for generation of waterfall plots and the impact of measurement error in generating them. We reviewed published waterfall plots to investigate variability in criteria used to define them. We then compared waterfall plots generated by different observers for 24 patients enrolled in a completed phase I study of solid tumors with available computed tomography (CT) scans. Tumor measurements were made independently from CT scans according to Response Evaluation Criteria in Solid Tumors 1.1 by four board-certified radiologists and four medical oncologists. Interobserver variability was quantified and compared with reference measurements reported for the phase 1 study. All statistical tests were two-sided. There was substantial variability in criteria used to generate published waterfall plots. In the internal study, the results were statistically significantly different between all eight readers (P = .01, variance = 197.1, SD = 14.0) and between the oncologists (P = .01, variance = 319.0, SD = 17.9), but not between the radiologists (P = .68, variance = 70.8, SD = 8.4). Different observers classified one to five patients as having a partial response and 12–19 patients as having stable disease. Similar variability in categorization of response was observed when these error rates were applied to published waterfall plots. Waterfall plots are subject to substantial variability in criteria used to define them and are influenced by measurement errors; they should be generated by trained radiologists. Caution should be exercised when interpreting results of waterfall plots in the context of clinical trials.
Coexisting Pneumocystis carinii pneumonia, cytomegalovirus pneumonitis and salmonellosis in systemic lupus erythematosus.
Authors: K H Leong, M L Boey, P H Feng
Journal: Annals of the Rheumatic Diseases (1991)

Infection with opportunistic organisms, either singly or in combination, is known to occur in immunocompromised patients. A patient with systemic lupus erythematosus who developed Pneumocystis carinii pneumonia, cytomegalovirus pneumonitis, and salmonellosis is reported. She responded to early treatment with intravenous trimethoprim-sulphamethoxazole (20 mg/kg).
Insights into the Origin of Metazoan Filopodia and Microvilli
Authors: Arnau Sebé-Pedrós, Pawel Burkhardt, Núria Sánchez-Pons, Stephen R. Fairclough, B. Franz Lang, Nicole King, Iñaki Ruiz-Trillo
Journal: Molecular Biology and Evolution (2013)

Filopodia are fine actin-based cellular projections used for both environmental sensing and cell motility, and they are essential organelles for metazoan cells. In this study, we reconstruct the origin of metazoan filopodia and microvilli. We first report on the evolutionary assembly of the filopodial molecular toolkit and show that homologs of many metazoan filopodial components, including fascin and myosin X, were already present in the unicellular or colonial progenitors of metazoans. Furthermore, we find that the actin crosslinking protein fascin localizes to filopodia-like structures and microvilli in the choanoflagellate Salpingoeca rosetta. In addition, homologs of filopodial genes in the holozoan Capsaspora owczarzaki are upregulated in filopodia-bearing cells relative to those that lack them. Therefore, our findings suggest that proteins essential for metazoan filopodia and microvilli are functionally conserved in unicellular and colonial holozoans and that the last common ancestor of metazoans bore a complex and specific filopodial machinery.
5-HT<sub>2</sub> and D<sub>2</sub> Receptor Occupancy of Olanzapine in Schizophrenia: A PET Investigation
Authors: S Kapur, R B Zipursky, G Remington, C Jones, J DaSilva, A A Wilson, S Houle
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. METHOD: Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30–40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. RESULTS: Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5–20 mg/day showed 43%–80% D2 occupancy, while patients taking 30–40 mg/day showed 83%–88%. CONCLUSIONS: Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10–20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects. (Am J Psychiatry 1998; 155:921–928)
In vivo optical imaging of integrin αV-β3 in mice using multivalent or monovalent cRGD targeting vectors
Authors: Zhao-Hui Jin, Véronique Josserand, Stéphanie Foillard, Didier Boturyn, Pascal Dumy, Marie-Christine Favrot, Jean-Luc Coll
Journal: Molecular Cancer (2007)

Abstract Background The cRGD peptide is a promising probe for early non-invasive detection of tumors. This study aimed to demonstrate how RAFT-c(-RGDfK-) 4 , a molecule allowing a tetrameric presentation of cRGD, improved cRGD-targeting potential using in vivo models of α V β 3 -positive or negative tumors. Results We chose the human embryonic kidney cells HEK293(β 3 ) (high levels of α V β 3 ) or HEK293(β 1 ) (α V β 3 -negative but expressing α V and β1) engrafted subcutaneously (s.c.) in mice. Non-invasive in vivo optical imaging demonstrated that as compared to its monomeric cRGD analogue, Cy5-RAFT-c(-RGDfK-) 4 injected intravenously had higher uptake, prolonged retention and markedly enhanced contrast in HEK293(β 3 ) than in the HEK293(β 1 ) tumors. Blocking studies further demonstrated the targeting specificity and competitive binding ability of the tetramer. Conclusion In conclusion, we demonstrated that Cy5-RAFT-c(-RGDfK-) 4 was indeed binding to the α V β 3 receptor and with an improved activity as compared to its monomeric analog, confirming the interest of using multivalent ligands. Intravenous injection of Cy5-RAFT-c(-RGDfK-) 4 in this novel pair of HEK293(β 3 ) and HEK293(β 1 ) tumors, provided tumor/skin ratio above 15. Such an important contrast plus the opportunity to use the HEK293(β 1 ) negative control cell line are major assets for the community of researchers working on the design and amelioration of RGD-targeted vectors or on RGD-antagonists.
Diaphragm Function during Sighs in Awake Dogs after Laparotomy
Authors: HISAKO KATAGIRI, MASATO KATAGIRI, TERESA M. KIESER, PAUL A. EASTON
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Pulmonary complications after upper abdominal surgery are usually ascribed to temporary postoperative impairment of diaphragm function, which may not originate from intrinsic, structural injury but from reflex inhibition of diaphragm contractility. Spontaneous breathing is interrupted periodically by sighs, even after upper abdominal surgery. If postoperative dysfunction of the diaphragm arises from a reflexic inhibition, then the sigh should temporarily override the inhibition and restore normal diaphragm function. We implanted sonomicrometer and electromyogram transducers chronically in six dogs by laparotomy, then directly measured length, shortening, and electromyogram activity of costal and crural diaphragm segments, parasternal intercostal, and transversus abdominis muscles an average of 8.7 (range, 1–16) d later during resting tidal breathing and sighs. In each animal we analyzed a sequence of breaths, including a sigh, when costal or crural diaphragm contractility was abnormal. With each sigh, the shape and amplitude of costal and crural diaphragm segmental shortening improved abruptly, from 0.9 and 1.4% of baseline length (% LBL) during resting breathing to 12.1 and 11.1% LBL, respectively, during sighs. The sighs were compared to CO2-stimulated breaths of equivalent tidal volume, which did not show either pattern or amplitude of shortening equivalent to sighs. We conclude that diaphragm dysfunction after laparotomy arises from a reflex inhibition, which is overridden abruptly to return diaphragm function briefly to normal during each spontaneous sigh.
Airway clearance research in CF: the ‘perfect storm’ of strong preference and effortful participation in long-term, non-blinded studies
Authors: Eleanor Main
Journal: Thorax (2013)

The global evolution of airway clearance techniques (ACTs) for cystic fibrosis (CF) and other respiratory disorders, with corresponding research, spans over four decades. Over this era, different ACTs have been invented, modified, retained or rejected. Some involve airway oscillation, some are independently performed and others require electricity or physical assistance. Some have strong geographical dominance, often more closely related to the origin of the technique and the strength of marketing, than to best evidence.

There has also been dramatic progress in the design, quality and rigour of research conducted to identify best practice. The best evidence from a plethora of early, underpowered, short-term studies (1–14 days in length), typically cross-over design, has been synthesised in five Cochrane reviews related to ACTs for CF, published between 2000 and 2011.1–6 All conclude that there is currently insufficient evidence to suggest superiority of any one technique. The calls for properly conducted, long-term, randomised controlled trials (RCTs) with standardised and meaningful outcome measures have intensified.

This study by McIlwaine et al answers the call elegantly.7 It is a well-designed, properly funded, long-term RCT. Results suggest that patients on high-frequency chest wall oscillation (HFCWO) therapy had more exacerbations than those on positive expiratory pressure (PEP) mask therapy, and they had them sooner. Given the substantive cost and marketing behind HFCWO (over 200 times more expensive than PEP mask therapy), these results provide important and clinically useful information that clinicians will find very helpful in making cost-effective and best practice decisions about airway clearance for their patients.7 In a landscape of ACT comparison literature, which invariably concludes that one technique or device is ‘equivalent’ to another, this is a noteworthy finding.1–6

In addition however, apart from confirming the difficulty of reaching recruitment targets, this study illuminates effectively two other challenges facing airway clearance …
Occupational exposure in ANCA-positive patients: A case-control study
Authors: Séverine Beaudreuil, Gérard Lasfargues, Laurence Lauériere, Zen El Ghoul, Florence Fourquet, Cédric Longuet, Jean-Michel Halimi, Hubert Nivet, Matthias Büchler
Journal: Kidney International (2005)
At What Cost Does a Potential Survival Advantage of Bevacizumab Make Sense for the Primary Treatment of Ovarian Cancer? A Cost-Effectiveness Analysis
Authors: David E. Cohn, Kenneth H. Kim, Kimberly E. Resnick, David M. O'Malley, J. Michael Straughn
Journal: Journal of Clinical Oncology (2011)

To determine whether the addition of bevacizumab to paclitaxel and carboplatin for the primary treatment of advanced ovarian cancer can be cost effective.A cost-effectiveness analysis compared the three arms of the Gynecologic Oncology Group (GOG) 218 study (paclitaxel plus carboplatin [PC], PC plus bevacizumab [PCB], and PCB plus bevacizumab maintenance [PCB+B]). Actual and estimated costs of treatment plus the potential costs of complications were established for each strategy. Progression-free survival (PFS) and bowel perforation rates were taken from recently reported results of GOG 218. Sensitivity analysis was performed for pertinent uncertainties in the model. Incremental cost-effectiveness ratios (ICERs) per progression-free life-year saved (PF-LYS) were estimated.For the 600 patients entered onto each arm of GOG 218 at the baseline estimates of PFS and bowel perforation, the cost of PC was $2.5 million, compared with $21.4 million for PCB and $78.3 million for PCB+B. These costs led to an ICER of $479,712 per PF-LYS for PCB and $401,088 per PF-LYS for PCB+B. When the cost of bevacizumab was reduced to 25% of baseline, the ICER of PCB+B fell below $100,000 per PF-LYS. ICERs were not substantially reduced when the perforation rate was equal across all arms.The addition of bevacizumab to standard chemotherapy in patients with advanced ovarian cancer is not cost effective. Treatment with maintenance bevacizumab leads to improved PFS but is associated with both direct and indirect costs. The cost effectiveness of bevacizumab in the adjuvant treatment of ovarian cancer is primarily dependent on drug costs.
Variability of peak flow in wheezy children.
Authors: I Johnston, H R Anderson, S Patel
Journal: Thorax (1984)

A study of peak flow variability was carried out among a population sample of 63 wheezy children aged 9-11 years. Recordings were made over 12 days at three times during the day--first thing in the morning, on returning home from school and at bedtime. Eighty nine per cent of the children had symptoms during the diary period. The mean amplitude (difference between the highest and lowest daily peak flow values) was 17% of the mean daily value (range 4-48%). By cosinor analysis the amplitude was 12% of the mean value (range 1-53%). In 65% of the children the lowest point of the daily rhythm as determined by cosinor analysis lay between midnight and 8am; the rhythm was, however, statistically significant in only fourteen individuals (22%). These levels of variability are considerably lower than those previously reported in hospital based studies of adult asthmatics. As a method of demonstrating variable airflow obstruction, which is the defining physiological characteristic of asthma, the use of a peak flow diary alone appears to be of limited value in children.
Deletion Polymorphisms in the Angiotensin Converting Enzyme Gene Are Associated with Pulmonary Hypertension Evoked by Exercise Challenge in Patients with Chronic Obstructive Pulmonary Disease
Authors: HIROSHI KANAZAWA, TAKASHI OKAMOTO, KAZUTO HIRATA, JUNICHI YOSHIKAWA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Angiotensin converting enzyme (ACE) plays an important role in the pathogenesis of pulmonary hypertension. In this study we determined whether the deletion (D)/insertion (I) polymorphism in the ACE gene may be associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease (COPD). ACE genotypes were determined in 19 patients with COPD. All patients underwent right heart catheterization followed by a constant-load exercise test while breathing room air or oxygen. Subgroups were created of seven patients with the II genotype, six with the ID genotype, and six with the DD genotype who were well-matched with respect to age, blood gas data at rest or after exercise, baseline lung function, results of incremental exercise testing, and hemodynamic data at rest. The mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (Rpv) at rest in the three subgrpoups did not differ significantly during breathing of either room air or oxygen. However, the Ppa after exercise challenge in patients with the DD genotype (55.7 +/- 4.9 mm Hg [mean +/- SD]) was significantly higher than in patients with the II genotype (42.6 +/- 7.1 mm Hg, p = 0.008). The Rpv after exercise in patients with the DD genotype was also significantly higher than in patients with the ID and II genotypes. During breathing of oxygen to diminish acute hypoxic pulmonary vasoconstriction, the Ppa in patients with the DD genotype (52.3 +/- 3.1 mm Hg) was higher than in patients with the ID genotype (40.5 +/- 5.9 mm Hg, p = 0.0049) or the II genotype (37.7 +/- 5.9 mm Hg, p = 0.0027). In addition, the Rpv in patients with the DD genotype was higher than in patients with the ID and II genotypes. These results suggest that D-I polymorphism in the ACE gene may be associated with pulmonary hypertension evoked by exercise challenge in patients with COPD. However, the number of patients in this study was very small for a genetic association study, and our results should be examined in larger studies.
Is the chemical prevention of gingivitis necessary to prevent severe periodontitis?
Authors: A Sheiham
Journal: Periodontology 2000 (1997)

Gingival inflammation seldom causes discomfort, social embarrassment or loss of function. As most sites with gingival inflammation do not progress to severe periodontal disease, gingivitis should not be considered a public health problem. Periodontitis is always preceded by gingivitis. But most gingivitis remains stable for years without progressing to periodontitis. The number of gingivitis sites that do convert is small. The levels of oral cleanliness achieved by the majority of populations in industrialized countries are below the threshold for severe destructive periodontal disease of personal and public health concern. Because methods of measuring the progression of periodontal disease are unreliable, definitive answers regarding conversion of gingivitis to severe periodontitis are lacking. Gingival inflammation frequently remains contained; most gingivitis remains stable for years without progressing to periodontitis. Decreasing gingivitis does reduce shallow pocketing, but the effect on severe periodontitis is not clear. Although the underlying justification for the reduction of plaque is to reduce gingival inflammation to prevent or reduce severe periodontitis and tooth loss, the basis for the approach is equivocal. A reasonably high level of plaque appears to be compatible with acceptably low levels of periodontal disease. Reducing nonspecific plaque levels to such levels is therefore a rational goal. The conventional methods of controlling periodontal disease involve mechanical removal of plaque and calculus. A complimentary ecological approach, using chemicals, would be to alter the environment of the pocket to prevent growth of putative pathogens. Any ecological approach should be sensitive to the dangers of disrupting the natural ecology of dental plaque. Some antimicrobial and antimetabolic agents such as fluoride, chlorhexidine and triclosan and zinc citrate can selectively suppress certain organisms or inhibit bacterial proteases implicated in tissue damage. The uncertainties about factors that convert gingival inflammation into periodontitis and periodontitis into severe periodontitis coupled with insufficient data from controlled clinical trials on the effectiveness of chemical reduction of gingivitis to prevent severe periodontitis leads one to conclude that more research is required before the need for the chemical prevention of gingivitis to prevent severe periodontitis can be justified.
Paclitaxel, Estramustine Phosphate, and Carboplatin in Patients With Advanced Prostate Cancer
Authors: William Kevin Kelly, Tracy Curley, Susan Slovin, Glenn Heller, John McCaffrey, Dean Bajorin, Allison Ciolino, Kevin Regan, Morton Schwartz, Philip Kantoff, Daniel George, William Oh, Matthew Smith, Donald Kaufman, Eric J. Small, Lawrence Schwartz, Steve Larson, William Tong, Howard Scher
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m 2 ), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m 2 without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.