tbuckley/cabot-search huggingface dataset:
Bevacizumab in Patients with Nonsquamous Non–Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized, Phase II Study
Authors: Benjamin Besse, Sylvestre Le Moulec, Julien Mazières, Hélène Senellart, Fabrice Barlesi, Christos Chouaid, Eric Dansin, Henri Bérard, Lionel Falchero, Radj Gervais, Gilles Robinet, Anne-Marie Ruppert, Roland Schott, Hervé Léna, Christelle Clément-Duchêne, Xavier Quantin, Pierre Jean Souquet, Jean Trédaniel, Denis Moro-Sibilot, Maurice Pérol, Anne-Catherine Madroszyk, Jean-Charles Soria
Journal: Clinical Cancer Research (2015)

The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non-small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup.Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0-1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m(2)) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages.In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7-7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0-8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae.The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases.
Role of capillary endothelium in the clearance of chylomicrons. A model for lipid transport from blood by lateral diffusion in cell membranes.
Authors: R O Scow, E J Blanchette-Mackie, L C Smith
Journal: Circulation Research (1976)

TABLE 1 Composition of Chylomicrons (Rat) Component Core Triglyceridc Cholesteryl ester Surface film Phospholipid (lecithin) Cholesterol Protein Triglyceride Diglyceride Monoglyceride Fatty acids Amount %of total 92.40 0.08 4.60 0.24 0.60 0.10 1.80 0.04 0.14 %of surface film --61.23.2 8.0 1.3 23.9 0.5 1.9 Bated on analyse* of chylomicron isolated from thoracic duct lymph of raU tube-fed com oil. 1 -•• "• " Values are expressed as percentage of weight.apoC-II, 32 and its action on triglyceride is suppressed in hypertonic NaCl s o l u t i o n ." ' 4 "Recent studies have shown that lipoprotein lipase has positional specificity for the primary ester bonds of glycerides."- 40The enzyme readily hydrolyzes triglyceride and l,2(2,3)-diglyceride to 2-monoglyceride and FFA, and 1(3)monoglyceride to glycerol and FFA, but has no effect on 2-monoglyceride.Thus, complete hydrolysis of triglyceride to glycerol and FFA by lipoprotein lipase requires isomerization of 2-monoglyceride to l(3)-monoglyceride.Lipoprotein lipase also hydrolyzes the primary acyl ester bond of lecithin to form 2-acyl lysolecithin. 41This isomer differs from that formed by LCAT" and phospholipase A,, 42 1-acyl lysolecithin.The fate of 2-acyl lysolecithin has not been studied. Uptake of Chylomicron Triglyceride by Extrahepatic TissuesTriglyceride fatty acids in chylomicrons are rapidly cleared from the blood when injected intravenously.The rate of clearance and fate of the fatty acids, however, depends on the nutritional and physiological state of the animal. 4'" 4 * In fed rats, about 32% of the fatty acids removed from blood in 10 minutes were found in adipose tissue, 32% in skeletal muscle, 18% in liver, and about 2% each in heart, kidney. TABLE 2 Protein Composition of Chylomicron-Very Low Density Lipoprotein (VLDL) Fraction Isolated from Rat Intestinal LymphApoprotein A-I A-II B C-I C-II C-I 11 % of total protein 30 7.5 35 2.5 7.5 17.5
Tumor-Specific CD8+ T Cells Expressing Interleukin-12 Eradicate Established Cancers in Lymphodepleted Hosts
Authors: Sid P. Kerkar, Pawel Muranski, Andrew Kaiser, Andrea Boni, Luis Sanchez-Perez, Zhiya Yu, Douglas C. Palmer, Robert N. Reger, Zachary A. Borman, Ling Zhang, Richard A. Morgan, Luca Gattinoni, Steven A. Rosenberg, Giorgio Trinchieri, Nicholas P. Restifo
Journal: Cancer Research (2010)

T-cell-based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers ( approximately 20 million) of tumor-specific T cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that approximately 10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12-engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8(+) T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4(+) Foxp3(+) T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells.
Adaptive Clinical Trial Designs for Simultaneous Testing of Matched Diagnostics and Therapeutics
Authors: Howard I. Scher, Shelley Fuld Nasso, Eric H. Rubin, Richard Simon
Journal: Clinical Cancer Research (2011)

Abstract A critical challenge in the development of new molecularly targeted anticancer drugs is the identification of predictive biomarkers and the concurrent development of diagnostics for these biomarkers. Developing matched diagnostics and therapeutics will require new clinical trial designs and methods of data analysis. The use of adaptive design in phase III trials may offer new opportunities for matched diagnosis and treatment because the size of the trial can allow for subpopulation analysis. We present an adaptive phase III trial design that can identify a suitable target population during the early course of the trial, enabling the efficacy of an experimental therapeutic to be evaluated within the target population as a later part of the same trial. The use of such an adaptive approach to clinical trial design has the potential to greatly improve the field of oncology and facilitate the development of personalized medicine. Clin Cancer Res; 17(21); 6634–40. ©2011 AACR.
Synchronized brain activity and neurocognitive function in patients with low-grade glioma: A magnetoencephalography study
Authors: Ingeborg Bosma, Linda Douw, Fabrice Bartolomei, Jan J. Heimans, Bob W. van Dijk, Tjeerd J. Postma, Cornelis J. Stam, Jaap C. Reijneveld, Martin Klein
Journal: Neuro-Oncology (2008)

We investigated the mechanisms underlying neurocognitive dysfunction in patients with low-grade glioma (LGG) by relating functional connectivity revealed by magnetoencephalography to neurocognitive function. We administered a battery of standardized neurocognitive tests measuring six neurocognitive domains to a group of 17 LGG patients and 17 healthy controls, matched for age, sex, and educational level. Magnetoencephalography recordings were conducted during an eyes-closed "resting state," and synchronization likelihood (a measure of statistical correlation between signals) was computed from the delta to gamma frequency bands to assess functional connectivity between different brain areas. We found that, compared with healthy controls, LGG patients performed more poorly in psychomotor function, attention, information processing, and working memory. LGG patients also had significantly higher long-distance synchronization scores in the delta, theta, and lower gamma frequency bands than did controls. In contrast, patients displayed a decline in synchronization likelihood in the lower alpha frequency band. Within the delta, theta, and lower and upper gamma bands, increasing short- and long-distance connectivity was associated with poorer neurocognitive functioning. In summary, LGG patients showed a complex overall pattern of differences in functional resting-state connectivity compared with healthy controls. The significant correlations between neurocognitive performance and functional connectivity in various frequencies and across multiple brain areas suggest that the observed neurocognitive deficits in these patients can possibly be attributed to differences in functional connectivity due to tumor and/or treatment.
Insulin resistance and daytime sleepiness in patients with sleep apnoea
Authors: A Barcelo, F Barbe, M de la Pena, P Martinez, J B Soriano, J Pierola, A G N Agusti
Journal: Thorax (2008)

Excessive daytime sleepiness (EDS), obesity and insulin resistance (IR) occur frequently in patients with obstructive sleep apnoea syndrome (OSAS). We hypothesised that in these patients, EDS is a marker of IR, independent of obesity.We studied 44 patients with OSAS (22 with and 22 without EDS) matched for age (+/-5 years), body mass index (BMI +/-3 kg/m(2)) and severity of OSAS (as determined by the apnoea-hypopnoea index (AHI)), and 23 healthy controls. Patients (n = 35) were re-examined after 3 months of effective therapy with continuous positive airway pressure (CPAP). EDS was assessed by both subjective (Epworth Sleepiness Scale) and objective (Multiple Sleep Latency Test) methods. IR was determined by the HOMA index. Serum levels of glucose, triglycerides, cholesterol, cortisol, insulin, thyrotropin, growth hormone and insulin-like growth factor I (IGF-I) were also determined.Despite the fact that age, BMI and AHI were similar, patients with EDS had higher plasma levels of glucose (p<0.05) and insulin (p<0.01), as well as evidence of IR (p<0.01) compared with patients without EDS or healthy controls. CPAP treatment reduced cholesterol, insulin and the HOMA index and increased IGF-1 levels in patients with EDS, but did not modify any of these variables in patients without EDS.EDS in OSAS is associated with IR, independent of obesity. Hence EDS may be a useful clinical marker to identify patients with OSAS at risk of metabolic syndrome.
Thalidomide and Hematopoietic-Cell Transplantation for Multiple Myeloma
Authors: Bart Barlogie, Guido Tricot, Elias Anaissie, John Shaughnessy, Erik Rasmussen, Frits van Rhee, Athanasios Fassas, Maurizio Zangari, Klaus Hollmig, Mauricio Pineda-Roman, Choon Lee, Giampaolo Talamo, Raymond Thertulien, Elias Kiwan, Somashekar Krishna, Michele Fox, John Crowley
Journal: New England Journal of Medicine (2006)

High-dose therapy with melphalan can prolong survival among patients with multiple myeloma. We assessed whether the addition of thalidomide, which has activity against advanced and refractory myeloma, would further improve survival.Between October 1998 and February 2004, 668 patients with newly diagnosed multiple myeloma received two cycles of intensive melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation. A total of 323 were randomly assigned to receive thalidomide from the outset until disease progression or undue adverse effects, and 345 did not receive thalidomide. The primary end point was the five-year event-free survival rate. Secondary end points were complete response and overall survival.After a median follow-up of 42 months among survivors, the thalidomide and control groups had rates of complete response of 62 percent and 43 percent, respectively (P<0.001), and five-year event-free survival rates of 56 percent and 44 percent (P=0.01). The five-year rate of overall survival was approximately 65 percent in both groups (P=0.90). Median survival after relapse was 1.1 years in the thalidomide group and 2.7 years in the control group (P=0.001). Severe peripheral neuropathy and deep-vein thrombosis occurred more frequently in the thalidomide group than in the control group.When incorporated into high-dose therapy for myeloma, thalidomide increased the frequency of complete responses and extended event-free survival at the expense of added adverse effects without improving overall survival. (ClinicalTrials.gov number, NCT00083551.).
Power-line frequency electromagnetic fields do not induce changes in phosphorylation, localization, or expression of the 27-kilodalton heat shock protein in human keratinocytes.
Authors: Biao Shi, Behnom Farboud, Richard Nuccitelli, R Rivkah Isseroff
Journal: Environmental Health Perspectives (2002)

The linkage of the exposure to the power-line frequency (50-60 Hz) electromagnetic fields (EMF) with human cancers remains controversial after more than 10 years of study. The in vitro studies on the adverse effects of EMF on human cells have not yielded a clear conclusion. In this study, we investigated whether power-line frequency EMF could act as an environmental insult to invoke stress responses in human keratinocytes using the 27-kDa heat shock protein (HSP27) as a stress marker. After exposure to 1 gauss (100 micro T) EMF from 20 min to 24 hr, the isoform pattern of HSP27 in keratinocytes remained unchanged, suggesting that EMF did not induce the phosphorylation of this stress protein. EMF exposure also failed to induce the translocation of HSP27 from the cytoplasm to the nucleus. Moreover, EMF exposure did not increase the abundance of HSP27 in keratinocytes. In addition, we found no evidence that EMF exposure enhanced the level of the 70-kDa heat shock protein (HSP70) in breast or leukemia cells as reported previously. Therefore, in this study we did not detect any of a number of stress responses in human keratinocytes exposed to power-line frequency EMF.
Unusual cause of lethal pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.
Authors: D Pittet, T Huguenin, S Dharan, J Sztajzel-Boissard, G Ducel, J B Thorens, R Auckenthaler, J C Chevrolet
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Two patients admitted to two different medical wards of our institution following respiratory decompensation of chronic obstructive pulmonary disease (COPD) were subsequently transferred to the same room of the medical intensive care unit (ICU) and intubated. Both patients developed invasive pulmonary aspergillosis and died soon after. Because COPD itself is rarely associated with lethal pulmonary aspergillosis, both cases were reviewed, and a retrospective investigation was conducted. Both patients had repeated sputum cultures while on the medical ward before their admission to the ICU; none of the sample grew Aspergillus spp. A. fumigatus was found in tracheal aspirates of both patients from the first day of their intubation while in the ICU. The pulmonary condition of both patients worsened, and invasive aspergillosis was diagnosed by bronchoalveolar lavage. Despite therapy with amphotericin B, the patients died 16 and 22 d after intubation, respectively. Both deaths were attributed to pulmonary aspergillosis; autopsy confirmed a massive pneumonia of the five lobes due to A. fumigatus in one patient. Investigation revealed that an air filter had been replaced 30 h before the first patient was admitted to the room. Experimental air filter replacement performed 12 d after the second patient died revealed the presence of A. fumigatus on the surface of the filters as well as a 10-fold increase in room air fungal counts during the procedure. This study shows that exposure to high concentrations of airborne Aspergillus spp. related to air filter change was associated with fatal invasive aspergillosis in two mechanically ventilated patients. Such infection can be prevented by the establishment and application of guidelines for air filter replacement.
Divergence of exonic splicing elements after gene duplication and the impact on gene structures
Authors: Zhenguo Zhang, Li Zhou, Ping Wang, Yang Liu, Xianfeng Chen, Landian Hu, Xiangyin Kong
Journal: Genome biology (2009)

Abstract Background The origin of new genes and their contribution to functional novelty has been the subject of considerable interest. There has been much progress in understanding the mechanisms by which new genes originate. Here we examine a novel way that new gene structures could originate, namely through the evolution of new alternative splicing isoforms after gene duplication. Results We studied the divergence of exonic splicing enhancers and silencers after gene duplication and the contributions of such divergence to the generation of new splicing isoforms. We found that exonic splicing enhancers and exonic splicing silencers diverge especially fast shortly after gene duplication. About 10% and 5% of paralogous exons undergo significantly asymmetric evolution of exonic splicing enhancers and silencers, respectively. When compared to pre-duplication ancestors, we found that there is a significant overall loss of exonic splicing enhancers and the magnitude increases with duplication age. Detailed examination reveals net gains and losses of exonic splicing enhancers and silencers in different copies and paralog clusters after gene duplication. Furthermore, we found that exonic splicing enhancer and silencer changes are mainly caused by synonymous mutations, though nonsynonymous changes also contribute. Finally, we found that exonic splicing enhancer and silencer divergence results in exon splicing state transitions (from constitutive to alternative or vice versa), and that the proportion of paralogous exon pairs with different splicing states also increases over time, consistent with previous predictions. Conclusions Our results suggest that exonic splicing enhancer and silencer changes after gene duplication have important roles in alternative splicing divergence and that these changes contribute to the generation of new gene structures.
Binding sites for bacterial and endogenous retroviral superantigens can be dissociated on major histocompatibility complex class II molecules.
Authors: J Thibodeau, N Labrecque, F Denis, B T Huber, R P Sékaly
Journal: The Journal of Experimental Medicine (1994)

Bacterial and retroviral superantigens (SAGs) interact with major histocompatibility complex (MHC) class II molecules and stimulate T cells upon binding to the V beta portion of the T cell receptor. Whereas both types of molecules exert similar effects on T cells, they have very different primary structures. Amino acids critical for the binding of bacterial toxins to class II molecules have been identified but little is known of the molecular interactions between class II and retroviral SAGs. To determine whether both types of superantigens interact with the same regions of MHC class II molecules, we have generated mutant HLA-DR molecules which have lost the capacity to bind three bacterial toxins (Staphylococcus aureus enterotoxin A [SEA], S. aureus enterotoxin B [SEB], and toxic shock syndrome toxin 1 [TSST-1]). Cells expressing these mutated class II molecules efficiently presented two retroviral SAGs (Mtv-9 and Mtv-7) to T cells while they were unable to present the bacterial SAGs. These results demonstrate that the binding sites for both types of SAGs can be dissociated.
Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells
Authors: François Mach, Alain Sauty, Albert S. Iarossi, Galina K. Sukhova, Kuldeep Neote, Peter Libby, Andrew D. Luster
Journal: Journal of Clinical Investigation (1999)

Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture, suggesting that they may play an important role in the pathogenesis of atherosclerosis. Moreover, atherosclerotic lesions contain the Th1-type cytokine IFN-γ, a potentiator of atherosclerosis. The present study demonstrates the differential expression of the 3 IFN-γ–inducible CXC chemokines — IFN-inducible protein 10 (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T-cell α chemoattractant (I-TAC) — by atheroma-associated cells, as well as the expression of their receptor, CXCR3, by all T lymphocytes within human atherosclerotic lesions in situ. Atheroma-associated endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages (MØ) all expressed IP-10, whereas Mig and I-TAC were mainly expressed in ECs and MØ, as detected by double immunofluorescence staining. ECs of microvessels within lesions also expressed abundant I-TAC. In vitro experiments supported these results and showed that IL-1β, TNF-α, and CD40 ligand potentiated IP-10 expression from IFN-γ–stimulated ECs. In addition, nitric oxide (NO) treatment decreased IFN-γ induction of IP-10. Our findings suggest that the differential expression of IP-10, Mig, and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions during atherogenesis.
Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A
Authors: Yasushi Kawaguchi, Masako Hara, Timothy M. Wright
Journal: Journal of Clinical Investigation (1999)

It is reported that fibroblasts derived from clinically affected skin areas of patients with systemic sclerosis (SSc) have the ability to overproduce several cytokines and growth factors (i.e., IL-6, PDGF), an ability that might be involved in the pathogenesis of SSc. We have previously shown that the expression of IL-1alpha was constitutively observed in SSc fibroblasts, whereas this was not detected in normal fibroblasts. Although it was suggested that the aberrant IL-1alpha production could be associated with the fibrogenic phenotype of SSc fibroblasts, little is known about the roles of IL-1alpha in SSc fibroblasts. IL-1alpha induced IL-6 and PDGF-A, which are potent stimulators of collagen production and proliferation in normal fibroblasts. This article examines the proposal that IL-6 and PDGF-A are elevated through the action of endogenous IL-1alpha in SSc fibroblasts. An antisense oligodeoxynucleotide complementary to IL-1alpha mRNA was used to suppress endogenous IL-1alpha. Inhibition of endogenous IL-1alpha led to decreased levels of IL-6 and PDGF-A expression in SSc fibroblasts. Moreover, the blocking of the IL-6 response using anti-IL-6 antibody resulted in a significant reduction of procollagen type I in cultured SSc fibroblasts. These results suggest that endogenous IL-1alpha expressed by SSc fibroblasts may play a key role in the abnormal function of SSc fibroblasts through the expression of IL-6 and PDGF-A.