tbuckley/cabot-search huggingface dataset:
Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest
Authors: Lea Schaaf, Matthias Schwab, Christoph Ulmer, Simon Heine, Thomas E. Mürdter, Jens O. Schmid, Georg Sauer, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2016)

Abstract Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868–75. ©2016 AACR.
Mitochondrial DNA Variation in Field Crickets across a Narrow Hybrid Zone
Authors: Richard Harrison, David Rand, Ward Wheeler2, Richard Corson Hall
Journal: Molecular Biology and Evolution (1987)

We have examined mitochondrial DNA (mtDNA) restriction-site variation within and between populations of fall-adult field crickets across a narrow hybrid zone in Connecticut.Our analysis reveals two distinct mtDNA lineages, each consisting of a single common genotype together with one or more rare genotypes.Outside the hybrid zone, the association between mtDNA genotype and species designation is nearly perfect.The A lineage corresponds to Gryllus pennsylvanicus and the B lineage to G. firmus.However, two G. firmus individuals from a coastal Connecticut population carry the A mtDNA genotype.Within the hybrid zone, the association between morphological characters, enzyme genotypes, and mtDNA genotypes breaks down to varying degrees.We compare patterns of introgression for these three types of markers.Previous authors have suggested that the behavior of mtDNA in hybrid zones may be different from that of nuclear-gene markers.We argue that differences in behavior are probably quantitative, not qualitative, and depend on the genetic architecture of speciation.We also document patterns of mtDNA length variation and associated heteroplasmy in both the A and B mtDNA lineages.The existence of identical size classes in both lineages suggests that the mutation rate for generating length variants is high.Therefore, genome size may not be a reliable marker of common ancestry.1.
Abstract 16031: Docosahexaenoic Acid Prevents Cardiac Dysfunction in Heart Failure, and Increases Mitochondrial Membrane Fluidity, Ca2+ Uptake, and Resistance to Permeability Transition
Authors: Kelly A OConnell, Erinne R Dabkowski, Rogerio F Ribeiro, Wenhong Xu, Tatiana Galvao, William C Stanley
Journal: Circulation (2012)

Treatment with docosahexaenoic acid (DHA, 22:6n3), a marine n-3 polyunsaturated fatty acid, has protective effects in patients and rodent models of heart failure (HF), however the mechanism of thes...
Informed consent and tardive dyskinesia
Authors: I Kleinman, D Schachter, E Koritar
Journal: American Journal of Psychiatry (1989)

To determine whether a formalized informing process transmitted knowledge concerning the risks and benefits of neuroleptic medication, particularly the risk of tardive dyskinesia, to stable schizophrenic outpatients, the authors administered a multiple-choice questionnaire to 21 patients who were read a standardized information form and 27 patients who were not. The mean scores for the informed patients were significantly higher, and the differences between the two groups remained significant at 6-month follow-up. The information process had no adverse effects on frequency of psychiatric admission, noncompliance with medication, or the need for increased antipsychotic medication.
Driving allotolerance: CAR-expressing Tregs for tolerance induction in organ and stem cell transplantation
Authors: Matthias Edinger
Journal: Journal of Clinical Investigation (2016)

Regulatory T cells (Tregs) modulate the function of a variety of immune cells and are critical for maintaining self-tolerance and preventing the development of autoimmune disease. Due to their ability to suppress effector T cells, Tregs have been increasingly explored for clinical use to suppress alloresponses. While this approach has been promising in preclinical models and early clinical trials, widespread clinical use of Tregs has been limited by the low number of these cells in the periphery and the unknown frequency of allo-responsive Tregs. In this issue of the JCI, MacDonald and colleagues transduced human Tregs with a chimeric antigen receptor (CAR) that targets the HLA class I molecule A2. These CAR-expressing T cells were readily activated via CAR stimulation and exerted potent immunosuppressive effects when stimulated in vitro. In a murine model of hematopoietic stem cell transplantation, CAR-modified Tregs were more effective in preventing the development of graft-versus-host disease compared with polyclonal Tregs. The results of this study lay the groundwork for the further evaluation of CAR-expressing Tregs in the prevention or treatment of transplant complications.
First-line chemotherapy for malignant peripheral nerve sheath tumor (MPNST) versus other histologic soft tissue sarcoma (STS) subtypes and as a prognostic factor for MPNST: An EORTC Soft Tissue and Bone Sarcoma Group (STBSG) study.
Authors: J. R. Kroep, M. Ouali, H. Gelderblom, A. Le Cesne, T. J. Dekker, M. M. Van Glabbeke, P. Hohenberger, P. C. Hogendoorn
Journal: Journal of Clinical Oncology (2010)

10074 Background: The role of chemotherapy in advanced MPNST is unclear. Promising results on two patients with locally-advanced MPNST treated with neoadjuvant chemotherapy encouraged us to retrospectively study the EORTC-STBSG data series, aiming to determine whether patients with advanced MPNST had a better outcome than those with advanced STS with other histotypes. Additionally, prognostic factors within the MPNST population were defined. Methods: Chemotherapy-naive STS patients treated on 12 pooled non-randomized and randomized trials of the EORTC-STBSG were retrospectively analysed. Clinical outcomes, overall-survival, progression-free-survival (PFS) and response, were recorded in the categories MPNST versus other histotypes. Studied cofactors were age, gender, performance status, sarcoma history, disease extent and chemotherapy-regimen. Results: After a median follow-up of 4.1 years, 175 MPNST patients out of 2675 eligible patients with advanced STS were analysed. Clinical outcome was similar for MPNST versus other histotype STS, with a response-rate of 21% versus 22%, median PFS of 17 versus 16 weeks and median overall-survival of 48 (95%CI:42-54) versus 51 (95%CI:49-53) weeks, respectively. Performance status was an independent prognostic factor for overall-survival. Chemotherapy regimen was an independent prognostic factor for both response (p<0.0001; logistic multivariate analysis) and PFS (p=0.009; cox multivariate analysis). Compared to anthracycline monotherapy, the anthracycline-ifosfamide treatment had the best PFS (HR=0.81;95%CI:0.48-1.36) and response-rate (HR=6.28;95%CI:2.34-16.85) whereas ifosfamide had the worst prognosis (HR=2.02;95%CI:1.16-3.33 and HR=0.33;95%CI:0.04-2.91, respectively). Conclusions: This EORTC-STBSG series indicated the role of chemotherapy in treatment of advanced MPNST. Patients with advanced MPNST had a similar outcome as other histotype STS. The apparent superiority of PFS with the anthracyclin-ifosfamide regimen justifies further investigations of this combination in randomized trials. No significant financial relationships to disclose.
Bereaved Caregiver Perspectives on the End-of-Life Experience of Patients With a Left Ventricular Assist Device
Authors: Colleen K. McIlvennan, Jacqueline Jones, Larry A. Allen, Keith M. Swetz, Carolyn Nowels, Daniel D. Matlock
Journal: JAMA Internal Medicine (2016)

For patients and their loved ones, decisions regarding the end of life in the setting of chronic progressive illness are among the most complex in health care. Complicating these decisions are increasingly available, invasive, and potentially life-prolonging technologies such as the left ventricular assist device (LVAD).To understand the experience of bereaved caregivers and patients at the end of life who have an LVAD.Semistructured, in-depth interviews were conducted between September 10 and November 21, 2014, with 8 bereaved caregivers of patients with an LVAD who were recruited from a single institution. Data were analyzed from December 13, 2014, to February 18, 2015, using a mixed inductive and deductive approach.Themes from semistructured interviews.The 8 caregivers (6 females) described 3 main themes that coalesced around feelings of confusion in the final weeks with their loved ones: (1) the process of death with an LVAD, (2) the legal and ethically permissible care of patients with an LVAD approaching death, and (3) fragmented integration of palliative and hospice care.Despite increasing use of LVADs in patients with advanced heart failure, bereaved caregivers of patients with an LVAD describe a high level of confusion at the end of life. There remains a need for the health care community to develop clear guidance on the management of patients with an LVAD at the end of life. Future work will focus on the educational process and the ideal timing and reiteration of such information to patients and families.
Remember malaria, even after a year
Authors: C. Godden
Journal: BMJ (1995)

EDITOR,--The guidelines for prophylaxis against malaria for travellers from Britain mention reports of vivax malaria resistant to chloroquine in Oceania and recommend vigilance for a year after the travellers have returned from malarious regions.1 I worked as a locum paediatrician in Papua New Guinea for three months, leaving there in January 1990 and arriving in England (via Australia, Indonesia, Thailand, Singapore, and Egypt) in May 1990.

I developed a …
The molecular evolution of bacterial alkaline phosphatase: correlating variation among enteric bacteria to experimental manipulations of the protein.
Authors: R F DuBose, D L Hartl
Journal: Molecular Biology and Evolution (1990)

The phylogenetic distribution of the gene coding for bacterial alkaline phosphatase @hoA) was examined in nine species of enteric bacteria closely related to Escherichiu coli.The nucleotide and protein sequences from the E. fergusonii and Serratia marcescens genes are presented.The spatial distribution of replaced amino acid residues in the aligned sequences is shown to be highly nonrandom and can be correlated with specific regions within the tertiary structure of the protein.There is an avoidance of replacements within the beta sheet of the protein, and there is an excess of replacements elsewhere, particularly in solvent-exposed residues.In addition, all positions across alpha helices do not accept replacements with equal frequency; there is a bias toward acceptance of replacements in the carboxyl ends of helices.To examine this further, mutations within the E. coli p/10,4 gene were created using site-directed mutagenesis.The patterns seen from the sequence comparisons were verified in the laboratory-created mutants.The average activity of mutations within or near the beta sheet was approximately one-third of that within or near alpha helices, and multiple mutations within the carboxyl ends of alpha helixes always possessed greater activity than did multiple mutations within the corresponding amino ends.The results indicate that identifiable regions within the protein are under different selective pressures and are therefore evolving at different rates.
PTH-337 Personalising radiotherapy in locally advanced rectal cancer: can macrophages within the microenvironment predict response to radiotherapy?
Authors: S Shaikh, A Noshirwani, NP West, SL Perry, T Maisey, DG Jayne
Journal: Gut (2015)

<h3>Introduction</h3> While neoadjuvant radiotherapy is the standard of care in locally invasive rectal carcinoma (LIRC), only half of patients show a response. A predictive test enabling better patient selection could avoid unneccessary radiation exposure to poor responders. Macrophages within the tumour immune microenvironment with tumoricidal M1 and tumour-protective M2 phenotypes could be modulating this response. This study investigated the possible predictive value of M1 and M2 subpopulations in identifying patients’ likely response to short-course preoperative radiotherapy. <h3>Method</h3> Biopsy samples were taken from 29 patients with locally invasive rectal carcinoma before treatment with short course radiotherapy and surgical specimens obtained after resection following short-course preoperative radiotherapy. Dual-staining immunohistochemistry was performed with CD68 as macrophage marker, HLA-DR as M1 marker, and CD163 as M2 marker. Samples were scored for hot-and-random spots by Nuance software (version 3.0.2) and compared with patients’ outcome data. Tumour response was measured by assessment of reduction of tumour-cell density. <h3>Results</h3> Samples revealing a low score for HLA-DR positive M1 macrophages exhibited a better response to short-course radiotherapy with up to 80% (median 80·38% [IQR 46·94–84·73]) reduction in the tumour cell density. On the other hand those with a high score exhibited a poor response with only up to 20% (20·26 [0–48·19]) reduction. The difference in response between the two groups was significant (p = 0·017). No such trends were observed for CD163<sup>+</sup>M2 macrophages. The ratio of HLA–DR+ to CD163<sup>+</sup>macrophages for biopsy and resection samples was significantly different showing a drop in the HLA-DR positive macrophages in the resection samples (p 0.024). The mean of the difference between the biopsy (median 2·53 [IQR 1.98 – 3.08]) and resection (1·38 [IQR 0.96 – 1.8]) was 1·15 (p = 0·024). <h3>Conclusion</h3> Patients with a variable macrophage phenotype composition within biopsy samples from patients with locally invasive rectal carcinoma respond differently to short-course preoperative radiotherapy. Further investigation involving a panel of macrophage and other immune-cell markers could verify and validate these findings and develop them as predictive tests identifying good responders to radiotherapy in patients with locally invasive rectal carcinoma. <h3>Disclosure of interest</h3> None Declared.
Hepatic-specific PPARα-FGF21 action in NAFLD
Authors: Elena Piccinin, Antonio Moschetta
Journal: Gut (2016)

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease in the Western countries affecting 20%–30% of the general population. NAFLD is considered as one of the manifestations of the metabolic syndrome, closely associated with obesity and type 2 diabetes, and may range from steatosis to the more aggressive form of non-alcoholic steatohepatitis (NASH). Long-standing NASH may progress in severe form of liver diseases, such as cirrhosis and hepatocellular carcinoma.

Steatosis in the liver is characterised by a large intracytoplasmic or well-defined fat droplets accumulation, displacing the nucleus to the cell periphery. Abnormal hepatic triglyceride accumulation is due to dysregulation of fatty acid metabolism. In healthy conditions, fatty acids are preferably stored in adipose tissue. However, elevated peripheral fatty acids together with hepatic de novo lipogenesis and defective apolipoprotein biosynthesis lead to hepatic lipid accumulation.

In this issue, Guillou and colleagues identify a novel hepatic-specific mechanism in the pathogenesis of NAFLD that directly involves the fatty acid sensor peroxisome proliferation-activated receptor α (PPARα) and the hormone fibroblast growth factor 21 (FGF21).1 

PPARs are ligand-activated transcription factors belonging to the nuclear receptor subfamily. They act as lipid sensors, regulating almost every aspect of lipid metabolism. Functional impairment or dysregulation of these receptors leads to obesity, fatty liver and type 2 diabetes. Although the three PPAR isoforms (α, β/δ and γ) share structural similarity and high homology sequence, they are …
Treatment of Hamster Pancreatic Cancer With α-Difluoromethylornithine, an Inhibitor of Polyamine Biosynthesis&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M Marx, C M Townsend, S C Barranco, E J Glass, J C Thompson
Journal: JNCI Journal of the National Cancer Institute (1987)

Polyamines are essential for cell division and growth. Inhibition of polyamine biosynthesis by α-difluoromethylornithine (DFMO) on the growth of hamster H2T pancreatic cancer was investigated both in vitro and in vivo. Cell-doubling time (TD) and survival fraction were determined after a single treatment with DFMO (5 mM).We examined the ability of putrescine to reverse the growth-inhibitory effect of DFMO. The TD for cells treated with DFMO in vitro was 49.6±5.7 versus 25.4±2.6 hours for control. The addition of putrescine to DFMO-treated H2T cells showed a reversal of the growth-inhibitory effect of DFMO. Cytotoxicity in vitro increased with prolonged treatment; the survival fraction after 24 hours of treatment was 32%; after 48 hours, 19%; after 72 hours, 13%; and after 92 hours, 8%. We performed two separate animal experiments. In experiment I, H2T cells were injected into the cheek pouch of male Syrian golden hamsters; controls did not receive DFMO. Continuous treatment with 3% DFMO in the drinking water was begun 7 days before, on the day of, or 7 days after tumor cell injection. In experiment II, 4 groups were treated identically to those in experiment I. An additional group of 10 hamsters received 3% DFMO and no tumor, and another additional group of 10 hamsters were housed individually with 3% DFMO begun 7 days after tumor cell injection. Tumor size, body weight, water, and food intake were measured. DFMO treatment in vivo significantly inhibited tumor size and inhibited growth of pancreatic cancer by as much as 50% of control. Our results demonstrate a significant antiproliferative effect of DFMO on the growth of pancreatic adenocarcinoma both in vitro and in vivo.
O3.01 * PROGRESSION OF CAROTID INTIMA MEDIA THICKNESS AFTER RADIOTHERAPY: A PROSPECTIVE COHORT STUDY
Authors: J. Wilbers, L. Dorresteijn, R. Haast, F. Hoebers, W. Boogerd, E. van Werkhoven, H. Hansen, C. de Korte, A. Kappelle, E. van Dijk
Journal: Neuro-Oncology (2014)

INTRODUCTION: Carotid artery vasculopathy is a long-term complication of radiotherapy (RT) of the neck with an increased risk of cerebrovascular events. We investigated the change in carotid Intima Media Thickness (IMT) and the incidence of ischemic stroke in the first 7 years after RT. METHODS: We conducted a multicentre prospective cohort study among patients treated for Head and Neck Cancer (HNC). We assessed carotid Intima Media Thickness at baseline before and after RT with a median follow-up of 7 years. We also assessed cerebrovascular risk factors and incident vascular events. RESULTS: 48 HNC patients underwent IMT measurement at baseline and follow-up (median age 61 years, range 29-87). Mean IMT of the irradiated common carotid arteries was 0.64 mm at baseline and 0.74mm at follow-up (p = 0.002 for change). Mean delta IMT in the irradiated versus non-irradiated common carotid arteries was 0.11 and 0.02 mm (p = 0.03 for difference), respectively. In a subgroup of unilaterally irradiated patients mean change in common carotid IMT from baseline to follow-up was 0.06 mm in the irradiated artery and 0.02 mm in the non-irradiated artery (p = 0.18 for difference). Within a mean follow-up of 3 years after radiotherapy 10 patients had an ischemic event. In these patients mean common carotid IMT increase was 0.08 mm. CONCLUSION: Our study showed an increase in IMT in irradiated carotid arteries in the first 7 years after treatment of HNC, which was significantly larger than in non-irradiated arteries. Patients treated with RT for HNC have a high risk of future stroke. This knowledge needs to be used to improve diagnostic and preventive strategies.
Interleukin-4 (IL-4) and IL-13 Enhance the Effect of IL-1β on Production of IL-1 Receptor Antagonist by Human Primary Hepatocytes and Hepatoma HepG2 Cells: Differential Effect on C-Reactive Protein Production
Authors: Cem Gabay, Brandon Porter, Denis Guenette, Bahri Billir, William P. Arend
Journal: Blood (1999)
Extent of bronchioloalveolar pattern and expression of the epidermal growth factor receptor in surgically resected lung adenocarcinomas
Authors: I. J. Dahabreh, J. Janinis, E. A. Karagiani, A. Dountsis, K. Vasilikos, H. T. Spiliadi, I. J. Dahabreh
Journal: Journal of Clinical Oncology (2006)

20065 Background: An increasing number of studies are exploring relations between the bronchioloalveolar differentiation of adenocarcinomas and clinical, radiological and molecular parameters. We investigated the potential relation between the extent of the bronchioloalveolar carcinoma (BAC) component of adenocarcinomas and the expression of the epidermal growth factor receptor (EGFR) protein. Methods: We retrospectively reviewed data from all patients who underwent surgery for lung cancer in our hospital between February 1, 2001 and May 31, 2005 (n = 366), and in whom pathologic analysis had revealed an adenocarcinoma histologic subtype. Paraffin embedded tissue samples were retrieved and re-examined. Samples exhibiting either a pure BAC histology or a mixed adenocarcinoma histology with a &gt;50% BAC component (n = 46) were selected for EGFR expression analysis by immunohistochemical staining. Patient demographics, stage and tumor differentiation data were recorded. Histological analysis was carried out using the WHO 1999/2004 criteria for lung cancers. For EGFR expression evaluation, samples were assigned a score ranging from 0 to +3. Expression was considered positive when the score was +1 or higher. Statistical analysis was performed using the chi-square test. Results: Of the 46 tumor samples examined, 10 had a BAC component of 50–79% (group A), 18 had BAC component of 80–99% (group B) and 18 exhibited a pure BAC histology (group C). Male/female ratio was 61.3%/38.7%. Mean age at presentation was 61.6 years. Among group A, 4 patients were EGFR positive and 6 were EGFR negative. 16 group B patients were EGFR positive and 2 were EGFR negative. Similarly, 16 group C patients were EGFR positive and 2 were EGFR negative. This distribution suggests that EGFR is more often expressed with increasing BAC component (p = 0.0041). No correlation was observed between demographics and EGFR expression or the extent of BAC pattern. Conclusions: EGFR expression is related to the extent of the BAC component in adenocarcinomas, with statistical significance. Study of a larger number of patients and correlation of this finding with EGFR and Ras mutational status and responsiveness to therapy are warranted. No significant financial relationships to disclose.