tbuckley/cabot-search huggingface dataset:
Ethics of Phase 1 Oncology Studies
Authors: Manish Agrawal, Ezekiel J. Emanuel
Journal: JAMA (2003)

Phase 1 oncology trials are critical to improving the treatment of cancer. Critics have raised 2 fundamental ethical challenges about phase 1 cancer research: the paucity of benefits with substantial risks and poor-quality informed consent. Despite 3 decades of controversy about phase 1 oncology research, there is little critical analysis of the arguments or of the data relevant to these questions. Existing but old data reveal that about 5% of patients in phase 1 trials experience shrinkage of their tumor, with a 0.5% mortality rate. In some notable cases, patients in phase 1 trials have been cured or sustained long-term remissions. Limited data suggest that patients in phase 1 trials may have better quality of life than comparable patients receiving supportive care. More important, the risks and benefits of phase 1 trials are not clearly worse than risk-benefit ratios used by the US Food and Drug Administration to approve chemotherapeutic agents for clinical use. The objections based on informed consent are deficiencies of disclosure, understanding, and voluntariness. The available data do not support the claim that disclosure is deficient. Although studies evaluating patient understanding have substantial methodological problems, they demonstrate that more than 70% of patients understand that they may not directly benefit even when they hope they will personally benefit. Finally, a closer look at issues of voluntariness reveals that patients with advanced cancer who participate in phase 1 research may have a different set of values than do critics and are not coerced. Overall, it appears that phase 1 oncology trials satisfy the requirement for a favorable risk-benefit ratio and that patients who enroll provide adequate informed consent.
Insulin Resistance, Inflammatory Biomarkers, and Adipokines in Patients with Chronic Kidney Disease
Authors: Soledad García de Vinuesa, Marian Goicoechea, Julia Kanter, Marta Puerta, Victoria Cachofeiro, Vicente Lahera, Francisco Gómez-Campderá, José Luño
Journal: Journal of the American Society of Nephrology (2006)

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and no diabetes were administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data that were obtained from 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml x mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 92 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl; P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the administration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ARB therapy.
The 30 mg Dose of Fexofenadine HCl 6 mg/mL Suspension is Bioequivalent to the Marketed 30 mg Tablet in Healthy Adult Subjects under Fasted Conditions: a Randomized, Crossover, Open-label Study
Authors: D.N. Morrison, S. Sahasranaman
Journal: Journal of Allergy and Clinical Immunology (2007)
Safety and efficacy of ectoine inhalation solution in patients with inflammation and airway obstruction: The EFECT study
Authors: Roman Berndt, Ulrich Sydlik, Andreas Bilstein, Alessandra Marini, Thomas Jaenicke, Gabriele Seitner-Sorge, Sabine Stolz, Jean Krutmann, Ursula Krämer, Klaus Unfried
Journal: European Respiratory Journal (2012)

Introduction

Ectoine is a compatible solute used for symptomatic treatment of rhinitis allergica, inflammatory dermatoses and irritated epithelia. Results from different studies demonstrated the efficacy of ectoine in reducing inflammation in the airways. Based on the positive results of a trial with asthmatic patients a study was set up to evaluate Ectoine Inhalation Solution (EIL) in subjects with mild airway obstruction and inflammation.

Methods

The study was designed as double blind, placebo-controlled cross-over trial. Subjects were randomly assigned to EIL or placebo (0.9% saline). Primary endpoint was defined as reduction of inflammatory markers IL 8 and % neutrophilic granulocytes in sputum. Other sputum and breath condensate biomarkers were analysed. QoL and spirometry data were collected on visit days.

Results

Reduction of inflammatory markers IL8 and granulocytes was greater after treatment with Ectoin compared to placebo (12% for IL8, 29% for neutrophils). Statistical significance could not be demonstrated. However, total Nitrogen from sputum showed a significant reduction after Ectoin (35%, p=0.02). Other biomarkers included in the investigation indicated advantages for Ectoin (granulocytes), or placebo (TNFα, LTB4, CRP). Analysis of QoL and spirometry data did not show significance to support superiority of one of the treatment arms.

No indication for increased health risks could be detected.

Conclusions

Inhalation of Ectoin can reduce inflammatory markers and shows an excellent safety profile. The results of the EFECT study support the outcome of other studies that the membrane stabilizing Ectoin reduces epithelia derived inflammatory processes.
Iptakalim: a new or just another KCO?
Authors: A. D.T. Costa
Journal: Cardiovascular Research (2009)

This editorial refers to 'K ATP activation prevents progression of cardiac hypertrophy to failure induced by pressure overload via protecting endothelial function' by S. Gao et al., this issue. rdiac hypertrophy, especially left ventricular hypertrophy (LVH), is a major compensatory mechanism in response to pressure overload derived from hypertension.Also, tissue remodelling through LVH is known to lead to heart failure if the increased workload is sustained over a long period of time.In a nutshell, hypertension can result in hypertrophy which, if sustained, leads to heart failure.Hypertension is also a risk factor for vascular accidents leading to ischaemia.Endothelial cell (dys)function has been shown to play important roles in the pathophysiological events related to the establishment and progression of hypertensive heart disease.Nitric oxide (NO) production by endothelial cells inhibits the progression of cardiac hypertrophy, whereas endothelin generation promotes hypertrophy. 1 Actually, the imbalance between these two systems is one of the underlying causes of cardiac tissue remodelling.Antihypertensive drugs that increase NO generation or that inhibit endothelin production have been shown to decrease cardiac hypertrophy (mostly by decreasing LVH), thus preventing heart failure induced by a pressure overload. 2owever, despite intense research, drugs able to ameliorate hypertension and, at the same time, protect against the associated heart diseases are still lacking.A promising candidate in this area is iptakalim, a recently developed K þ channel opener (KCO) that has been shown to be antihypertensive in different models of hypertension in rats, dogs, and humans. 3,4his issue of Cardiovascular Research brings an interesting contribution to the field of hypertension and heart disease, uncovering some new properties of iptakalim.Gao et al. 5 show that iptakalim possesses antihypertrophic properties, preventing the progression of LVH to heart failure induced by pressure overload.They also show that iptakalim helps maintain several haemodynamic parameters, such as heart
Essays on the First Hundred Years of Anaesthesia
Authors: A. O'Donnell
Journal: BMJ (2008)

In many departments where I have worked there is a shelf in the library that contains old, dusty books about the history of anaesthesia. Browsing one day, I picked up one old book and found I could not put it down.

Born in 1894, William Stanley Sykes was an anaesthetist in Leeds before the second world war. He was captured and held as a prisoner of war in Greece for some years. At the end of the war he returned to civilian life to find that anaesthesia had evolved in the intervening years, and he considered his skills …
Immunology of Psoriasis
Authors: Michelle A. Lowes, Mayte Suárez-Fariñas, James G. Krueger
Journal: Annual Review of Immunology (2014)

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.
β-Lapachone-containing PEG–PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells
Authors: Elvin Blanco, Erik A. Bey, Ying Dong, Brent D. Weinberg, Damon M. Sutton, David A. Boothman, Jinming Gao
Journal: Journal of Controlled Release (2007)
Effects of capsaicin and bradykinin on afferent fibers with ending in skeletal muscle.
Authors: M P Kaufman, G A Iwamoto, J C Longhurst, J H Mitchell
Journal: Circulation Research (1982)

Capsaicin, injected into the arterial supply of the skinned hindlimb of dogs, evokes reflex increases in cardiovascular function. Moreover, the cardiovascular reflexes evoked by capsaicin are very similar to those evoked by static exercise. The afferent fibers initiating these reflex increases have not been identified electrophysiologically, although their endings are believed to be located in skeletal muscle. We have, therefore, attempted to determine which afferent fibers are stimulated by capsaicin. In anesthetized dogs, we recorded impulses from afferent fibers with endings in either the gastrocnemius or gracilis muscles and injected capsaicin (10-30 microgram/kg) into the abdominal aorta. Capsaicin stimulated 24 of 34 group IV (C fiber) endings, but only 5 of 19 group III (A delta fiber) endings. By contrast, bradykinin (0.5-1.5 microgram/kg) stimulated 17 of 33 group IV endings and 9 of 19 group III endings. Impulse activity for the 24 group IV afferents stimulated by capsaicin increased from 0.7 +/- 0.1 to a peak of 9.3 +/- 1.4 imp/sec. Firing started 6 +/- 1 seconds after injection and remained above control levels for 24 +/- 5 seconds. Capsaicin had no significant effect on the firing rate of 30 group I and II muscle afferents. Our results suggest that group IV muscle afferents are primarily responsible for causing the reflex increases in cardiovascular function evoked by injecting capsaicin into the arterial supply of the skinned hindlimb of dogs. Moreover, capsaicin is likely to be a useful pharmacological tool with which to determine the reflex autonomic effects caused by stimulation of group IV muscle afferents.
Methylseleninic Acid Potentiates Apoptosis Induced by Chemotherapeutic Drugs in Androgen-Independent Prostate Cancer Cells
Authors: Hongbo Hu, Cheng Jiang, Clement Ip, Youcef M. Rustum, Junxuan Lü
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To test whether and how selenium enhances the apoptosis potency of selected chemotherapeutic drugs in prostate cancer (PCA) cells. Experimental Design: DU145 and PC3 human androgen–independent PCA cells were exposed to minimal apoptotic doses of selenium and/or the topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38), the topoisomerase II inhibitor etoposide or the microtubule inhibitor paclitaxel/taxol. Apoptosis was measured by ELISA for histone-associated DNA fragments, by flow cytometric analysis of sub-G1 fraction, and by immunoblot analysis of cleaved poly(ADP-ribose)polymerase. Pharmacologic inhibitors were used to manipulate caspases and c-Jun-NH2-terminal kinases (JNK). Results: The methylselenol precursor methylseleninic acid (MSeA) increased the apoptosis potency of SN38, etoposide, or paclitaxel by several folds higher than the expected sum of the apoptosis induced by MSeA and each drug alone. The combination treatment did not further enhance JNK1/2 phosphorylation that was induced by each drug in DU145 cells. The JNK inhibitor SP600125 substantially decreased the activation of caspases and apoptosis induced by MSeA combination with SN38 or etoposide and completely blocked these events induced by MSeA/paclitaxel. The caspase-8 inhibitor zIETDfmk completely abolished apoptosis and caspase-9 and caspase-3 cleavage, whereas the caspase-9 inhibitor zLEHDfmk significantly decreased caspase-3 cleavage and apoptosis but had no effect on caspase-8 cleavage. None of these caspase inhibitors abolished JNK1/2 phosphorylation. A JNK-independent suppression of survivin by SN38 and etoposide, but not by paclitaxel, was also observed. In contrast to MSeA, selenite did not show any enhancing effect on the apoptosis induced by these drugs. Conclusions: MSeA enhanced apoptosis induced by cancer therapeutic drugs in androgen-independent PCA cells. In DU145 cells, the enhancing effect was primarily through interactions between MSeA and JNK-dependent targets to amplify the caspase-8-initiated activation cascades. The results suggest a novel use of methyl selenium for improving the chemotherapy of PCA.
A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas
Authors: Crystal L. Mackall, Eunice H. Rhee, Elizabeth J. Read, Hanh M. Khuu, Susan F. Leitman, Donna Bernstein, Merertu Tesso, Lauren M. Long, David Grindler, Margret Merino, William Kopp, Maria Tsokos, Jay A. Berzofsky, Lee J. Helman
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Patients with metastatic or recurrent Ewing’s sarcoma family of tumors and alveolar rhabdomyosarcoma have &amp;lt;25% 5-year survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. Experimental Design: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing’s sarcoma family of tumors or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2 (rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2. Results: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2+ patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients initiating immunotherapy. Conclusions: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic cells.
Spike Timing–Dependent Plasticity: A Hebbian Learning Rule
Authors: Natalia Caporale, Yang Dan
Journal: Annual Review of Neuroscience (2008)

Spike timing-dependent plasticity (STDP) as a Hebbian synaptic learning rule has been demonstrated in various neural circuits over a wide spectrum of species, from insects to humans. The dependence of synaptic modification on the order of pre- and postsynaptic spiking within a critical window of tens of milliseconds has profound functional implications. Over the past decade, significant progress has been made in understanding the cellular mechanisms of STDP at both excitatory and inhibitory synapses and of the associated changes in neuronal excitability and synaptic integration. Beyond the basic asymmetric window, recent studies have also revealed several layers of complexity in STDP, including its dependence on dendritic location, the nonlinear integration of synaptic modification induced by complex spike trains, and the modulation of STDP by inhibitory and neuromodulatory inputs. Finally, the functional consequences of STDP have been examined directly in an increasing number of neural circuits in vivo.
Protein Kinase D Is a Key Regulator of Cardiomyocyte Lipoprotein Lipase Secretion After Diabetes
Authors: Min Suk Kim, Fang Wang, Prasanth Puthanveetil, Girish Kewalramani, Elham Hosseini-Beheshti, Natalie Ng, Yanni Wang, Ujendra Kumar, Sheila Innis, Christopher G. Proud, Ashraf Abrahani, Brian Rodrigues
Journal: Circulation Research (2008)

The diabetic heart switches to exclusively using fatty acid (FA) for energy supply and does so by multiple mechanisms including hydrolysis of lipoproteins by lipoprotein lipase (LPL) positioned at the vascular lumen. We determined the mechanism that leads to an increase in LPL after diabetes. Diazoxide (DZ), an agent that decreases insulin secretion and causes hyperglycemia, induced a substantial increase in LPL activity at the vascular lumen. This increase in LPL paralleled a robust phosphorylation of Hsp25, decreasing its association with PKCdelta, allowing this protein kinase to phosphorylate and activate protein kinase D (PKD), an important kinase that regulates fission of vesicles from the golgi membrane. Rottlerin, a PKCdelta inhibitor, prevented PKD phosphorylation and the subsequent increase in LPL. Incubating control myocytes with high glucose and palmitic acid (Glu+PA) also increased the phosphorylation of Hsp25, PKCdelta, and PKD in a pattern similar to that seen with diabetes, in addition to augmenting LPL activity. In myocytes in which PKD was silenced or a mutant form of PKCdelta was expressed, high Glu+PA were incapable of increasing LPL. Moreover, silencing of cardiomyocyte Hsp25 allowed phorbol 12-myristate 13-acetate to elicit a significant phosphorylation of PKCdelta, an appreciable association between PKCdelta and PKD, and a vigorous activation of PKD. As these cells also demonstrated an additional increase in LPL, our data imply that after diabetes, PKD control of LPL requires dissociation of Hsp25 from PKCdelta, association between PKCdelta and PKD, and vesicle fission. Results from this study could help in restricting cardiac LPL translocation, leading to strategies that overcome contractile dysfunction after diabetes.
Randomized Study on the Efficacy of Cognitive-Behavioral Therapy for Insomnia Secondary to Breast Cancer, Part I: Sleep and Psychological Effects
Authors: Josée Savard, Sébastien Simard, Hans Ivers, Charles M. Morin
Journal: Journal of Clinical Oncology (2005)

Purpose Chronic insomnia is highly prevalent in cancer patients. Cognitive-behavioral therapy (CBT) is considered the treatment of choice for chronic primary insomnia. However, no randomized controlled study has been conducted on its efficacy for insomnia secondary to cancer. Using a randomized controlled design, this study conducted among breast cancer survivors evaluated the effect of CBT on sleep, assessed both subjectively and objectively, and on hypnotic medication use, psychological distress, and quality of life. Patients and Methods Fifty-seven women with insomnia caused or aggravated by breast cancer were randomly assigned to CBT (n = 27) or a waiting-list control condition (n = 30). The treatment consisted of eight weekly sessions administered in a group and combined the use of stimulus control, sleep restriction, cognitive therapy, sleep hygiene, and fatigue management. Follow-up evaluations were carried out 3, 6, and 12 months after the treatment. Results Participants who received the insomnia treatment had significantly better subjective sleep indices (daily sleep diary, Insomnia Severity Index), a lower frequency of medicated nights, lower levels of depression and anxiety, and greater global quality of life at post-treatment compared with participants of the control group after their waiting period. Results were more equivocal on polysomnographic indices. Therapeutic effects were well maintained up to 12 months after the intervention and generally were clinically significant. Conclusion This study supports the efficacy of CBT for insomnia secondary to breast cancer.