tbuckley/cabot-search huggingface dataset:
Interleukin-18: a potent pro-inflammatory cytokine in atherosclerosis: EXPERT'S PERSPECTIVE
Authors: L. Badimon
Journal: Cardiovascular Research (2012)

This editorial refers to an article by R. Elhage et al . [6][1] published in Cardiovascular Research in 2003. It is accompanied by a retrospective editorial by three of the authors of that original article, R. Elhage et al . (doi:10.1093/cvr/cvs220), as part of this Spotlight on Landmark Papers in Cardiovascular Research . 

The first report on interleukin-18 (IL-18) in patients with myocardial infarction (MI) triggered a significant interest in understanding the role of this cytokine, widely studied in other types of inflammatory diseases, in atherosclerosis.1 Stable and unstable human carotid atherosclerotic plaques were investigated, and it was found that IL-18 was highly expressed compared with control, normal arteries and that it was mainly localized in plaque macrophages.2 IL-18 receptor (IL-18R) was also up-regulated in plaque macrophages and endothelial cells (ECs), suggesting potential biological effects. Significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques as compared with asymptomatic (stable) plaques.2

Electrotransfer of an expression-plasmid DNA encoding murine IL-18-binding protein (BP) in Apo E−/− mice was shown to prevent atherosclerotic plaque progression, inducing changes in plaque composition [a decrease in macrophages, T cells, cell death, and lipid content and an increase in smooth muscle cell (SMC) and collagen content] and leading to a stable plaque phenotype.3 The expression of functional IL-18 and IL-18R was later reported on isolated ECs, SMCs, and macrophages, with the induction of interferon-γ (IFNγ) expression in SMCs.4 Next, studies in Apo E−/− mice showed that IL-18 administration enhanced atherosclerosis in the mouse ascending aorta and the aortic arch through the release of IFNγ.5

However, the IL-18 knockout proof-of-concept was still missing. The effect of blocking the endogenous production of IL18 upon a background of ongoing atherosclerosis progression remained unknown. This information was provided by the important study reported in the …

 [1]: #ref-6
Immunity to Neuroblastomas and Melanomas
Authors: K E Hellstrom, I Hellstrom
Journal: Annual Review of Medicine (1972)

This article will review studies on immune reactions to tumor-associated antigens (TAA) of two types of human neoplasms, neuroblastomas and malignant melanomas. The reason for choosing these tumors is that they belong to the few human neoplasms which undergo occasional spontaneous regressions (indicating that they may be immunologically rejected by their hosts), and that they are among those most investigated with respect to both cell-mediated and humoral i mmune reactions against TAA. Knowledge provided by studying i mmunity to these neoplasms may help us to under­ stand better host immunological defenses against other human tumors as well. Rather than trying to make a chronological account of what information has been obtained so as to establish priorities, we will discuss some of the principal findings which have evolved. Clinical evidence for host-mediated i mmune reactions against neuroblastomas and melanomas will be presented, and observations will be reviewed which show cell-mediated immune reac­ tions against these tumors.' We will summarize experiments demonstrating how lymphocyte-mediated destruction of neoplastic cells can be thwarted by blocking factors present in sera from tumor-bearing patients. and we will discuss reports on humoral antibodies to melanomas and neuroblastomas, detectable by i mmunofluorescence and cytotoxic tests. The nature of the antigens involved will be considered. Finally, we will speculate on what i mplications these immunological findings may have in relation to the three practical goals of cancer research: prevention, therapy, and diagnosis.
Prostaglandins and Hypercalcemic States
Authors: H W Seyberth, L G Raisz, J A Oates
Journal: Annual Review of Medicine (1978)

There is considerable circumstantial evidence to support the concept that prostaglandins of the E series can mediate hypercalcemia in neoplastic disease. However, other metabolites of prostaglandin endoperoxides could contribute to the hypercalcemia and the site of the production of prostaglandins is not established. Further analysis of prostaglandin endoperoxide metabolism in tumor and bone tissue and in the circulation will clarify the specific mechanism. The development of quantitative analysis of prostaglandin metabolites had made it possible to identify prostaglandin-dependent hypercalcemia. Therapeutic application of the inhibitors of prostaglandin cyclo-oxygenase in the treatment of patients with prostaglandin-mediated hypercalcemia is feasible, but its general usefulness remains to be evaluated. The development of antagonists to the action of prostaglandin at the affected end organ site, presumably bone, would represent an important therapeutic advance.
Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation.
Authors: J D Shepherd, L E Pringle, M J Barnett, H G Klingemann, D E Reece, G L Phillips
Journal: Journal of Clinical Oncology (1991)

Hemorrhagic cystitis is a major complication of high-dose cyclophosphamide therapy used in preparation for allogeneic or autologous bone marrow transplantation. Although previous reports had suggested that the sulfhydryl-containing compound mesna might be superior to forced diuresis in preventing hemorrhagic cystitis, there were concerns about the effect of mesna on engraftment in these studies. To address these concerns, 100 patients were randomized to receive mesna or forced saline diuresis while undergoing bone marrow transplant conditioning with regimens that included high-dose cyclophosphamide. To try to minimize the likelihood of graft rejection, patients who were being transplanted with cyclophosphamide as a sole agent were excluded from the study. After randomization and administration of therapy, patients were monitored by microscopic and dip-stick urinalyses; they were also followed for effects of therapy on engraftment. The incidence of consistent or severe hematuria was 33% in the mesna arm and 20% in the hyperhydration arm (P = .31). Severe bleeding occurred in 12.5% of mesna patients and 7.5% of hyperhydration patients (P = .71). No unexpected toxicities were encountered, and engraftment times did not differ. Based on this randomized trial of 100 patients, we conclude that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation patients.
Disentangling Sources of Selection on Exonic Transcriptional Enhancers
Authors: Rachel M. Agoglia, Hunter B. Fraser
Journal: Molecular Biology and Evolution (2015)

In addition to coding for proteins, exons can also impact transcription by encoding regulatory elements such as enhancers. It has been debated whether such features confer heightened selective constraint, or evolve neutrally. We have addressed this question by developing a new approach to disentangle the sources of selection acting on exonic enhancers, in which we model the evolutionary rates of every possible substitution as a function of their effects on both protein sequence and enhancer activity. In three exonic enhancers, we found no significant association between evolutionary rates and effects on enhancer activity. This suggests that despite having biochemical activity, these exonic enhancers have no detectable selective constraint, and thus are unlikely to play a major role in protein evolution.
Pharmacokinetic Pitfalls in the Estimation of the Breast Milk/Plasma Ratio for Drugs
Authors: J T Wilson, R D Brown, J L Hinson, J W Dailey
Journal: The Annual Review of Pharmacology and Toxicology (1985)

Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other ...Read More
Effect of Renal Dysfunction on Toxicity in Three Decades of Cancer Therapy Evaluation Program–Sponsored Single-Agent Phase I Studies
Authors: Jan H. Beumer, Fei Ding, Hussein Tawbi, Yan Lin, Diana Viluh, Indrani Chatterjee, Matthew Rinker, Selina L. Chow, S. Percy Ivy
Journal: Journal of Clinical Oncology (2015)

Alterations in renal clearance of anticancer drugs can affect the occurrence of toxicities related to drug exposure. The National Cancer Institute and the US Food and Drug Administration (FDA) use different criteria to classify renal dysfunction. We examined those discrepancies and their potential association with the incidence of toxicities in patients enrolled onto Cancer Therapy Evaluation Program-sponsored single-agent phase I studies over three decades (1979 to 2010).Data to estimate creatinine clearance according to the Cockcroft-Gault and Jelliffe formulas were available from 10,236 patients, and data to estimate creatinine clearance according to the six- and four-variable Modification of Diet in Renal Disease formulas were available from a subset (n = 4,084). Patients were classified according to National Cancer Institute and FDA criteria, and the rates of clinically relevant toxicities were evaluated within groups and compared among groups.Cockcroft-Gault estimated renal function improved over time, which may be attributed to an increase in weight of patients in the same time frame. Approximately 36% of patients enrolled onto phase I trials had mild renal dysfunction by FDA criteria. Relative to normal function, mild renal dysfunction was associated with a statistically significant but small increase in grade 3 or 4 nonhematologic toxicity and any relevant toxicities.Patients with mild renal dysfunction by FDA criteria have routinely been enrolled onto phase I studies of antineoplastics without clinically meaningful increase in the risk of toxicity. In future oncology renal dysfunction trials based on the FDA classification, the FDA mild group may only need to be activated when the moderate and normal groups differ substantially in tolerability or pharmacokinetics.
Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response
Authors: Kai Bartkowiak, Marcel Kwiatkowski, Friedrich Buck, Tobias M. Gorges, Lars Nilse, Volker Assmann, Antje Andreas, Volkmar Müller, Harriet Wikman, Sabine Riethdorf, Hartmut Schlüter, Klaus Pantel
Journal: Cancer Research (2015)

Abstract Disseminated tumor cells (DTC), which share mesenchymal and epithelial properties, are considered to be metastasis-initiating cells in breast cancer. However, the mechanisms supporting DTC survival are poorly understood. DTC extravasation into the bone marrow may be encouraged by low oxygen concentrations that trigger metabolic and molecular alterations contributing to DTC survival. Here, we investigated how the unfolded protein response (UPR), an important cytoprotective program induced by hypoxia, affects the behavior of stressed cancer cells. DTC cell lines established from the bone marrow of patients with breast cancer (BC-M1), lung cancer, (LC-M1), and prostate cancer (PC-E1) were subjected to hypoxic and hypoglycemic conditions. BC-M1 and LC-M1 exhibiting mesenchymal and epithelial properties adapted readily to hypoxia and glucose starvation. Upregulation of UPR proteins, such as the glucose-regulated protein Grp78, induced the formation of filamentous networks, resulting in proliferative advantages and sustained survival under total glucose deprivation. High Grp78 expression correlated with mesenchymal attributes of breast and lung cancer cells and with poor differentiation in clinical samples of primary breast and lung carcinomas. In DTCs isolated from bone marrow specimens from breast cancer patients, Grp78-positive stress granules were observed, consistent with the likelihood these cells were exposed to acute cell stress. Overall, our findings provide the first evidence that the UPR is activated in DTC in the bone marrow from cancer patients, warranting further study of this cell stress pathway as a predictive biomarker for recurrent metastatic disease. Cancer Res; 75(24); 5367–77. ©2015 AACR.
Gestational Age and Birth Weight and the Risk of Childhood Type 1 Diabetes: A Population-Based Cohort and Sibling Design Study
Authors: Ali S. Khashan, Louise C. Kenny, Cecilia Lundholm, Patricia M. Kearney, Tong Gong, Roseanne McNamee, Catarina Almqvist
Journal: Diabetes Care (2015)

OBJECTIVE We investigated the effects of gestational age, birth weight, small for gestational age (SGA), and large for gestational age (LGA) on risk of childhood type 1 diabetes. RESEARCH DESIGN AND METHODS We conducted a population-based cohort study of all singleton live births in Sweden between 1973 and 2009 and a sibling control study. Perinatal data were extracted from the Swedish Medical Birth Register. Children with type 1 diabetes diagnosis were identified from the Swedish National Patient Register. Log-linear Poisson regression and conditional logistic regression were used for data analysis. RESULTS The study cohort consisted of 3,624,675 singleton live births (42,411,054 person-years). There were 13,944 type 1 diabetes cases during the study period. The sibling control study consisted of 11,403 children with type 1 diabetes and 17,920 siblings. Gestational age between 33 and 36 weeks (relative risk [RR] 1.18 [95% CI 1.09, 1.28) and 37 and 38 weeks (RR 1.12 [95% CI 1.07, 1.17]) was associated with type 1 diabetes in the cohort study and remained significant in the sibling control study. SGA (RR 0.83 [95% CI 0.75, 0.93]) and LGA (RR 1.14 [95% CI 1.04, 1.24]) were associated with type 1 diabetes in the cohort study. The SGA association remained unchanged in the sibling study, while the LGA association disappeared. Very low birth weight was associated with a reduced risk of type 1 diabetes. CONCLUSIONS The findings suggest a small association between gestational age and type 1 diabetes that is not likely due to familial confounding factors. Gestational age and type 1 diabetes may be related to insulin resistance due to early life growth restriction or altered gut microbiota in preterm babies.
Addition of Statins to Treatment With β-Blockers to Improve Outcomes for Cardiac Surgery Patients
Authors: William Toppen, Sohail Sareh, Daniel Johansen, Bradley Genovese, Nancy Satou, Richard Shemin, Peyman Benharash
Journal: JAMA Surgery (2015)

For nearly 2 decades, β-blockers have been thought to reduce the risk of major adverse cardiovascular events during the perioperative period.Beginning with the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography trial 1 in 1999, a series of studies have provided compelling evidence that patients undergoing high-risk operations should receive β-blockers before surgery. 2 Given these findings, the Surgical Care Improvement Project required that all patients previously receiving β-blockers should receive their medication in the 24 hours before surgery.More recently, however, several large-scale studies have failed to reproduce these beneficial effects, 3,4 and the Perioperative Ischemic Evaluation trial 4 found increased mortality with the use of β-blockers before surgery.A similar controversy exists with regard to the perioperative administration of statins, agents that may reduce
Transfer Factor Therapy in Immune Deficiency States
Authors: Alan S. Levin, Lynn E. Spitler, H. Hugh Fundenberg
Journal: Annual Review of Medicine (1973)

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is ...Read More
Prospective Evaluation of the 21-Gene Recurrence Score Assay for Breast Cancer Decision-Making in Ontario
Authors: Mark N. Levine, Jim A. Julian, Philippe L. Bedard, Andrea Eisen, Maureen E. Trudeau, Brian Higgins, Louise Bordeleau, Kathleen I. Pritchard
Journal: Journal of Clinical Oncology (2015)

To evaluate the 21-gene recurrence score (RS) on decision-making in a population-based cohort.Patients with axillary node-negative or nodal micrometastases, estrogen receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer being considered for chemotherapy were eligible. All cancer treatment centers in Ontario, Canada, participated. Oncologists made a preliminary recommendation for endocrine therapy with or without chemotherapy on the basis of Adjuvant! Online (AOL) risk estimation. Patients were asked for their preference regarding chemotherapy. After RSs were available, patients returned for final decision-making. Patient satisfaction was measured by using the decisional conflict scale.Between January 2012 and July 2013, 1,000 patients were recruited. RSs were available for 979 patients. In 58% of patients, risk was categorized as low (RS, 0 to 18); in 33%, intermediate (RS, 19 to 30); and in 9%, high (RS, ≥ 31). Oncologists' recommendations pretest and post-test remained the same in 464 patients (48%), changed from unsure or chemotherapy to no chemotherapy in 365 (38%), and changed from unsure or no chemotherapy to chemotherapy in 143 (15%). After the test, oncologists recommended chemotherapy for 236 patients, 81% of whom received chemotherapy. Of 151 patients in whom risk was classified as intermediate by means of AOL, 41% were a low risk and 44% intermediate risk with RS. Of 298 patients at high risk with AOL, 16% had a high risk RS. None of 236 patients with grade I tumors had a high-risk RS. Mean total decisional conflict scale score significantly improved from pretest to post-test from 34 to 19 (P < .001).The RS substantially influenced both oncologists' recommendations and patients' preferences for chemotherapy. The major effect was avoidance of chemotherapy when AOL indicated high or intermediate risk.
What's hot that the other lot got
Authors: Janice Higginson
Journal: Thorax (2016)

It's 5 years since Ramsey et al 's landmark paper demonstrating Ivacaftors's ability to significantly change lung function in cystic fibrosis (CF) patients with the G551D mutation. The search is now on for a similar finding for the most common mutation—F508del. Although not as dramatic, Wainwright et al ( N Engl J Med 2015;373:220–31) have shown that combining a CF transmembrane conductance regulator (CFTR) corrector—Lumacafor—and a CFTR potentiator—Ivacaftor—does produce a significant improvement in FEV1.

The ban on smoking in a car carrying children will become UK law in October 2015; it is already law in some US states. Ahn et al ( J Paeds 2015; http://dx.doi.org/10.1016/j.jpeds.2015.06.049) add to the mounting evidence of the effect of secondhand smoke on children with their study of 2219 children admitted with pneumonia in Tennessee and Utah between 2010 and 2012. Children with ≥2 smokers in their household were more likely to go to an intensive …
Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia
Authors: Yu-Chou Tseng, Samuel K. Kulp, I-Lu Lai, En-Chi Hsu, Wei A. He, David E. Frankhouser, Pearlly S. Yan, Xiaokui Mo, Mark Bloomston, Gregory B. Lesinski, Guido Marcucci, Denis C. Guttridge, Tanios Bekaii-Saab, Ching-Shih Chen
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:Cancer cachexia is a debilitating condition that impacts patient morbidity, mortality, and quality of life and for which effective therapies are lacking. The anticachectic activity of the novel HDAC inhibitor AR-42 was investigated in murine models of cancer cachexia.
Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors
Authors: S Cerquozzi, A Tefferi
Journal: Blood Cancer Journal (2015)

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1 -negative myeloproliferative neoplasms and are characterized by relatively long median survivals (approximately 14 and 20 years, respectively). Potentially fatal disease complications in PV and ET include disease transformation into myelofibrosis (MF) or acute myeloid leukemia (AML). The range of reported frequencies for post-PV MF were 4.9–6% at 10 years and 6–14% at 15 years and for post-ET MF were 0.8–4.9% at 10 years and 4–11% at 15 years. The corresponding figures for post-PV AML were 2.3–14.4% at 10 years and 5.5–18.7% at 15 years and for post-ET AML were 0.7–3% at 10 years and 2.1–5.3% at 15 years. Risk factors cited for post-PV MF include advanced age, leukocytosis, reticulin fibrosis, splenomegaly and JAK2V617F allele burden and for post-ET MF include advanced age, leukocytosis, anemia, reticulin fibrosis, absence of JAK2V617F , use of anagrelide and presence of ASXL1 mutation. Risk factors for post-PV AML include advanced age, leukocytosis, reticulin fibrosis, splenomegaly, abnormal karyotype, TP53 or RUNX1 mutations as well as use of pipobroman, radiophosphorus (P 32 ) and busulfan and for post-ET AML include advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations. It is important to note that some of the aforementioned incidence figures and risk factor determinations are probably inaccurate and at times conflicting because of the retrospective nature of studies and the inadvertent labeling, in some studies, of patients with prefibrotic primary MF or ‘masked’ PV, as ET. Ultimately, transformation of MPN leads to poor outcomes and management remains challenging. Further understanding of the molecular events leading to disease transformation is being investigated.