Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment. \ud \u

The COS/UVES Absorption Survey of the Magellanic Stream: II. Evidence for a complex enrichment history of the Stream from the Fairall 9 sightline

We present a multi-wavelength study of the Magellanic Stream (MS), a massive gaseous structure in the Local Group that is believed to represent material stripped from the Magellanic Clouds. We use ultraviolet, optical and radio data obtained with HST/COS, VLT/UVES, FUSE, GASS, and ATCA to study metal abundances and physical conditions in the Stream toward the quasar Fairall 9. Line absorption in the MS from a large number of metal ions and from molecular hydrogen is detected in up to seven absorption components, indicating the presence of multi-phase gas. From the analysis of unsaturated SII absorption, in combination with a detailed photoionization model, we obtain a surprisingly high alpha abundance in the Stream toward Fairall 9 of [S/H]=-0.30pm0.04 (0.5 solar). This value is 5 times higher than what is found along other MS sightlines based on similar COS/UVES data sets. In contrast, the measured nitrogen abundance is found to be substantially lower ([N/H]=-1.15pm0.06), implying a very low [N/alpha] ratio of -0.85 dex. The substantial differences in the chemical composition of MS toward Fairall 9 compared to other sightlines point toward a complex enrichment history of the Stream. We favour a scenario, in which the gas toward Fairall 9 was locally enriched with alpha elements by massive stars and then was separated from the Magellanic Clouds before the delayed nitrogen enrichment from intermediate-mass stars could set in. Our results support (but do not require) the idea that there is a metal-enriched filament in the Stream toward Fairall 9 that originates in the LMC.Comment: Accepted for publication in ApJ; 20 pages, 11 figure

Relapsed and refractory primary CNS lymphoma: treatment approaches in routine practice

Despite recent therapeutic progress and improved survival for many patients with primary central nervous system lymphoma (PCNSL), up to 50% of patients will experience refractory or relapsed disease following first-line treatment with high dose methotrexate (HD-MTX) based regimens. The majority of such events occur within 2 years of diagnosis although, unlike their systemic counterpart, the risk of PCNSL relapse remains, even for patients in radiologic complete response at 10 years following diagnosis. Currently, there are no approved therapies, and no widely accepted ‘standard-of-care’ approaches for the treatment of refractory or recurrent primary central nervous system lymphoma (rrPCNSL). Re-treatment with HD-MTX based regimens, use of non-cross resistant chemotherapy regimens, high-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT), and brain irradiation all remain important therapeutic approaches for rrPCNSL. However, the survival outcomes for patients with rrPCNSL remain extremely poor and the vast majority of patients will die of their disease. Increasingly, novel treatment approaches are being investigated in early phase clinical studies. Importantly, such therapies need to be evaluated in the context of both refractory and relapsed disease; in older patients and those with co-morbid conditions; and those with neurocognitive dysfunction. A deeper understanding of the molecular genetic mechanisms underpinning rrPCNSL and its unique tumor microenvironment is urgently needed to inform biologically rational and effective therapies. rrPCNSL remains a clear unmet clinical need and a high priority area for clinical research that will require national and international collaborative studies with embedded translational science in order to improve outcomes for patients

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.

PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors

Repetitive Mild Traumatic Brain Injury Impairs Performance in a Rodent Assay of Cognitive Flexibility

Mild traumatic brain injury (mTBI) occurs in almost 80% of the 3 million reported cases of TBI-related emergency department visits each year in the United States. The majority of mTBIs, sometimes classified as concussions, are due to sports-related activities and typically occur repeatedly over the course of an athlete’s career. mTBI symptoms are generally classified as either somatic or neuropsychiatric/cognitive in nature and include impairments in prefrontal cortex mediated functions, including attention, memory, processing speed, reaction times, problem solving, and cognitive flexibility. To date, there remains a major gap in our understanding of the behavioral manifestations, underlying neurobiology, and treatment of mTBI. An even greater gap exists in our understanding of the consequences of repeated mTBI incidents. The goal of the present study was to examine the effects of repetitive mTBI within a rodent assay of cognitive flexibility. Rats were exposed to a series of three closed head injuries (controlled cortical impact model) within a week prior to performing an automated strategy shifting task, which required rats to learn and shift strategies according to changing task demands. Rats initially acquired a visual cue strategy in which a light illuminated above one of two possible levers (left or right) indicated the correct response for reward. Twenty-four hours after initial acquisition, rats again performed the task using the visual cue strategy followed by a series of strategy shifting and reversal learning challenges. Repetitive mTBI reduced throughput scores, a performance index that blends accuracy and response speed, and increased reaction times within the task. These results indicate that performance and task efficiency in an operant test of cognitive flexibility are impaired after repetitive mTBI. As such, this model presents a useful approach for further investigating the behavioral deficits and potential treatment strategies for patients who have experienced multiple mTBI insults

Identification of a Likely Radio Counterpart of the Rapid Burster

We have identified a likely radio counterpart to the low-mass X-ray binary MXB 1730-335 (the Rapid Burster). The counterpart has shown 8.4 GHz radio on/off behavior correlated with the X-ray on/off behavior as observed by the RXTE/ASM during six VLA observations. The probability of an unrelated, randomly varying background source duplicating this behavior is 1-3% depending on the correlation time scale. The location of the radio source is RA 17h 33m 24.61s; Dec -33d 23' 19.8" (J2000), +/- 0.1". We do not detect 8.4 GHz radio emission coincident with type II (accretion-driven) X-ray bursts. The ratio of radio to X-ray emission during such bursts is constrained to be below the ratio observed during X-ray persistent emission at the 2.9-sigma level. Synchrotron bubble models of the radio emission can provide a reasonable fit to the full data set, collected over several outbursts, assuming that the radio evolution is the same from outburst to outburst, but given the physical constraints the emission is more likely to be due to ~hour-long radio flares such as have been observed from the X-ray binary GRS 1915+105.Comment: 28 pages, 4 figures; accepted for publication in ApJ (no changes

Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF.

IntroductionPatient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.MethodsROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).ResultsA total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.ConclusionsStudy drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.FundingThe ROCKET AF trial was funded by Johnson & Johnson and Bayer

Illinois Waterfowl Surveys and Investigations W-43-R-62 Annual Progress Report Period: 1 July 2014 – 30 June 2015

This study addresses the following objectives: 1)Inventory abundance and distribution of waterfowl and other waterbirds (a minimum of 10 species and guilds) during autumn migration at a minimum of 40 sites along the Illinois and central Mississippi rivers; 2) Investigate the ecology of canvasback and lesser scaup during spring migration in the central Illinois River valley (IRV) and Pool 19 of the Mississippi River; 3) Estimate waterfowl and other waterbird population sizes (a minimum of 10 species and guilds) during autumn migration using an aerial quadrat survey in the IRV for comparison with aerial inventories (Objective 1); 4) Determine breeding bird use of a minimum of 10 moist-soil wetlands managed for waterfowl during summer in central Illinois; 5) Investigate the breeding ecology of sandhill cranes during spring and summer in northeastern Illinois; 6) Distribute our findings to site managers and biologists, make recommendations for future management, and draw conclusions relevant to regional conservation planning during the project period as appropriate and requested.Illinois Department of Natural Resources, Division of Wildlife & U.S. Fish and Wildlife Service Contract Number: RC09-13FWUIUCunpublishednot peer reviewedOpe