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The neurofibromatoses are a group of genetic disorders that cause development of nervous system tumors as well as various other tumor and systemic manifestations. Neurofibromatosis type 1 is the most prevalent of these conditions and has the most variable phenotype and highest risk of malignant tumor formation. Neurofibromatosis type 2 has no associated malignant tumors but does carry significant morbidity, including deafness, facial weakness, and physical disability. Schwannomatosis is the least prevalent of these disorders and is characterized primarily by nonvestibular schwannomas and pain.

Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.

Background Patients with PTSD often voice concern over their perceived change in cognitive functioning. However, these negative appraisals do not always align with objective neuropsychological performance, yet are strongly predictive of PTSD symptom severity and self-reported functional impairment. Methods The present study involves a secondary analysis examining the role of appraisals of a subsample of 81 adults with full or subthreshold PTSD on treatment outcomes in a randomized controlled trial investigating the effectiveness of a cognitive rehabilitation treatment, Strategic Memory and Reasoning Training (n = 38), compared to a psychoeducation control arm, the Brain Health Workshop (n = 43). Neither condition addressed PTSD symptoms, focusing instead on cognitive skills training and psychoeducation about the brain. Results Intent-to-treat models showed statistically significant improvements for both groups on composite scores of executive functioning and memory. Additionally, both groups experienced clinically significant reductions in PTSD symptoms (assessed via the Clinician-Administered PTSD Interview) and the SMART group showed fewer negative appraisals about cognitive functioning following training. Change in appraisals of cognitive functioning was associated with change in PTSD as well as change in quality of life, with no differential associations based on group status. In contrast, neurocognitive test score changes were not associated with change in symptoms or functional outcomes. Limitations We did not collect data on other appraisals (e.g., self-efficacy), which could have further elucidated pathways of change. Conclusions Our findings suggest that interventions that do not directly target PTSD symptoms can lead to PTSD symptom change via change in appraisals of functioning.

Background Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in patients with R/R AML, with the intention of applying sophisticated methods to predict responders. Methods Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on the understood mechanisms of azacitidine and lenalidomide in the setting of each patients’ disease. Findings Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively. Interpretation Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.

Cognitive models of depression suggest that depressed individuals exhibit a tendency to attribute negative meaning to neutral stimuli, and enhanced processing of mood-congruent stimuli. However, evidence thus far has been inconsistent. In this study, we sought to identify both differential interpretation of neutral information as well as emotion processing biases associated with depression. Fifty adult participants completed standardized mood-related questionnaires, a novel immediate mood scale questionnaire (IMS-12), and a novel task, Emotion Matcher, in which they were required to indicate whether pairs of emotional faces show the same expression or not. We found that overall success rate and reaction time on the Emotion Matcher task did not differ as a function of severity of depression. However, more depressed participants had significantly worse performance when presented with sad-neutral face pairs, as well as increased reaction times to happy-happy pairs. In addition, accuracy of the sad-neutral pairs was found to be significantly associated with depression severity in a regression model. Our study provides partial support for the mood-congruent hypothesis, revealing only a potential bias in interpretation of sad and neutral expressions, but not a general deficit in processing of facial expressions. The potential of such bias in serving as a predictor for depression should be further examined in future studies.

As the use of carbon-based nanomaterials (CNMs) in various consumer goods continues to rise, it is imperative that we accumulate a better understanding of their impact and fate in the environment. In particular, it is important to have an understanding of how these materials may affect plants as these organisms have both economic importance and an impact on human health. CNMs have exhibited both beneficial and toxic effects, as well as no effect, on plant growth and reproduction. Exposure to CNMs has also had an effect on oxidative stress, water channels, phytohormones, gene expression, and epigenetics. The present review briefly discusses the current understanding and knowledge gaps of how exposure to CNMs might lead to changes in plant growth and physiology by altering gene expressions and epigenomes.

Bubbling dynamics and distribution of gas flow critically influence the performance of fluidized bed reactors and must be quantified accurately for their design and performance optimization. In this study, a new toolset called the BubbleTree toolset (BT) was developed using Python and the Visualization Tool Kit (VTK) for analyzing computational fluid dynamics simulation data and performing statistical analysis of bubbling dynamics such as their volume, location, and velocity. In addition, the BT toolset provides the capability to (a) track bubbles through coalescence and splitting events and (b) compute throughflow by integrating gas fluxes through the bubble surface. The toolkit was verified using the method of manufactured solutions as well as by comparing bubbling dynamics predictions in large-scale simulations with relevant open-source software. The BT toolset also incorporates tools for rigorous statistical analysis in selected regions of interest as well as the reactor in its entirety. The BT will be integrated with MFiX CFD simulations which will enable the fundamental investigation of gas-solids flow interaction in complex reacting particulate flows, in situ estimation of bubbling (and cluster) dynamics dependent sub-grid models and performance optimization of fluidized bed reactors using CFD-simulations.

Calculation of the gas phase proton affinity of CH4, PA(CH4), involves characterisation of the CH5+ ion whose fluxional nature requires reevaluation of some assumptions routinely made for more normal molecules. Here we determine the PA(CH4; 0 K) using quantum diffusion Monte Carlo (QDMC) simulations on a previously developed CCSD(T)/aug-cc-pVTZ potential energy surface for CH5+. We obtain a value of 542.4 kJ/mol in reasonable agreement with the most recent measurements. The results obtained from standard thermochemical methods, and the limitations of these methods, are also discussed.

Background Multiple chronic health conditions have been associated with exposure to the September 11, 2001 World Trade Center (WTC) terrorist attacks (9/11). We assessed whether excess deaths occurred during 2003–2014 among persons directly exposed to 9/11, and examined associations of 9/11-related exposures with mortality risk. Materials and methods Deaths occurring in 2003–2014 among members of the World Trade Center Health Registry, a cohort of rescue/recovery workers and lower Manhattan community members who were exposed to 9/11, were identified via linkage to the National Death Index. Participants’ overall levels of 9/11-related exposure were categorized as high, intermediate, or low. We calculated standardized mortality ratios (SMR) using New York City reference rates from 2003 to 2012. Proportional hazards were used to assess associations of 9/11-related exposures with mortality, accounting for age, sex, race/ethnicity and other potential confounders. Results We identified 877 deaths among 29,280 rescue/recovery workers (3.0%) and 1694 deaths among 39,643 community members (4.3%) during 308,340 and 416,448 person-years of observation, respectively. The SMR for all causes of death was 0.69 [95% confidence interval (CI) 0.65–0.74] for rescue/recovery workers and 0.86 (95% CI 0.82–0.90) for community members. SMRs for diseases of the cardiovascular and respiratory systems were significantly lower than expected in both groups. SMRs for several other causes of death were significantly elevated, including suicide among rescue recovery workers (SMR 1.82, 95% CI 1.35–2.39), and brain malignancies (SMR 2.25, 95% CI 1.48–3.28) and non-Hodgkin's lymphoma (SMR 1.79, 95% CI 1.24–2.50) among community members. Compared to low exposure, both intermediate [adjusted hazard ratio (AHR) 1.36, 95% CI 1.10–1.67] and high (AHR 1.41, 95% CI 1.06–1.88) levels of 9/11-related exposure were significantly associated with all-cause mortality among rescue/recovery workers (p-value for trend 0.01). For community members, intermediate (AHR 1.13, 95% CI 1.01–1.27), but not high (AHR 1.14, 95% CI 0.94–1.39) exposure was significantly associated with all-cause mortality (p-value for trend 0.03). AHRs for associations of overall 9/11-related exposure with heart disease- and cancer-related mortality were similar in magnitude to those for all-cause mortality, but with 95% CIs crossing the null value. Conclusions Overall mortality was not elevated. Among specific causes of death that were significantly elevated, suicide among rescue/recovery workers is a plausible long-term consequence of 9/11 exposure, and is potentially preventable. Elevated mortality due to other causes, including non-Hodgkin's lymphoma and brain cancer, and small but statistically significant associations of 9/11-related exposures with all-cause mortality hazard warrant additional surveillance.

Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. Statement of Significance In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Summary Alternative splicing is a post-transcriptional regulatory mechanism producing distinct mRNA molecules from a single pre-mRNA with a prominent role in the development and function of the central nervous system. We used long-read isoform sequencing to generate full-length transcript sequences in the human and mouse cortex. We identify novel transcripts not present in existing genome annotations, including transcripts mapping to putative novel (unannotated) genes and fusion transcripts incorporating exons from multiple genes. Global patterns of transcript diversity are similar between human and mouse cortex, although certain genes are characterized by striking differences between species. We also identify developmental changes in alternative splicing, with differential transcript usage between human fetal and adult cortex. Our data confirm the importance of alternative splicing in the cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide transcript-level data for human and mouse cortex as a resource to the scientific community., Graphical abstract, Highlights • There is widespread transcript diversity in the cortex and many novel transcripts • Some genes display big differences in isoform number between human and mouse cortex • There is evidence of differential transcript usage between human fetal and adult cortex • There are many novel isoforms of genes associated with human brain disease, Leung et al. use long-read sequencing to annotate RNA isoforms in the human and mouse cortex. They identify novel transcripts and evidence for differential transcript usage between the fetal and adult cortex. Their data confirm the importance of alternative splicing as a mechanism underpinning gene regulation in the brain.

Melampomagnolide B (MMB, 3) is a parthenolide (PTL, 1) based sesquiterpene lactone that has been used as a template for the synthesis of a plethora of lead anticancer agents owing to its reactive C-10 primary hydroxyl group. Such compounds have been shown to inhibit the IKKβ subunit, preventing phosphorylation of the cytoplasmic IκB inhibitory complex. The present study focuses on the synthesis and in vitro antitumor properties of novel benzyl and phenethyl carbamates of MMB (7a-7k). Screening of these MMB carbamates identified analogs with potent growth inhibition properties against a panel of 60 human cancer cell lines (71% of the molecules screened had GI(50) values

A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a–3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a–4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d–3i and dimers 4f–4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28-33.5 μM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50 = 280–980 nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c–3l and 4b–4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h–3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1–8.1 μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1–109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control.

We developed a fast-neutron multiplicity counter based on organic scintillators (EJ-309 liquid and stilbene). The system detects correlated photon and neutron multiplets emitted by fission reactions, within a gate time of tens of nanoseconds. The system was used at Idaho National Laboratory to assay a variety of plutonium metal plates. A coincidence counting strategy was used to quantify the 240Pu effective mass of the samples. Coincident neutrons, detected within a 40-ns coincidence window, show a monotonic trend, increasing with the 240Pu-effective mass (in this work, we tested the 0.005–0.5 kg range). After calibration, the system estimated the 240Pu effective mass of an unknown sample (240Pueff >50 g) with an uncertainty lower than 1% in a 4-min assay time.

HIV infection and methamphetamine (METH) use are highly comorbid and represent a significant public health problem. Both conditions are known to negatively impact a variety of brain functions. One brain function that may be affected by HIV and METH use is sensorimotor gating, an automatic, pre-conscious filtering of sensory information that is thought to contribute to higher order cognitive processes. Sensorimotor gating is often measured using prepulse inhibition (PPI), a paradigm that can be conducted in both humans and animals, thereby enabling cross-species translational studies. While previous studies suggest HIV and METH may individually impair PPI, little research has been conducted on the effects of combined HIV and METH on PPI. The goal of this cross-species study was to determine the effects of METH on PPI in the inducible Tat (iTat) mouse model of HIV and in people with HIV. PPI was measured in the iTat mouse model before, during, and after chronic METH treatment and after Tat induction. Chronic METH treatment decreased PPI in male but not female mice. PPI normalized with cessation of METH. Inducing Tat expression decreased PPI in male but not in female mice. No interactions between chronic METH treatment and Tat expression were observed in mice. In humans, HIV was associated with decreased PPI in both men and women. Furthermore, PPI was lowest in people with HIV who also had a history of METH dependence. Overall, these results suggest HIV and METH may additively impair early information processing in humans, potentially affecting downstream cognitive function.HIGHLIGHTSHIV decreased PPI in men and womenPPI was most decreased in people with HIV and a history of METH dependenceChronic METH treatment decreased PPI in male but not female miceTat expression decreased PPI in male but not female miceChronic METH treatment and Tat expression did not interact to affect PPI in mice

Background Diabetes mellitus has been associated with significant perioperative complications in joint arthroplasty. In addition, many patients are unaware of their dysglycemic status, and the prevalence of undiagnosed dysglycemia in joint arthroplasty patients is unknown. Methods Several years ago, we began routine hemoglobin A1c (HbA1c) level screening in all our patients planning to undergo elective total hip and total knee arthroplasties. We retrospectively reviewed the HbA1c levels in our initial 663 patients. Results Forty-eight percent of these patients were found to be nondiabetic; 19% percent had a previous history of some level of dysglycemia. Most significantly, over one third, 33.6% of these patients were previously undiagnosed dysglycemic patients; 31% were diagnosed as prediabetic and 2.6% as diabetic. Conclusion Owing to the high prevalence of prediabetic patients who go on to develop diabetes and to the high correlation of poor glucose control with perioperative complications, we feel that it is imperative to identify this large number of previously undiagnosed dysglycemic patients. We recommend the routine screening of all patients planning to undergo major orthopedic procedures. Likewise, we recommend that identified patients be referred for diabetic counseling. We also recommend that patients with markedly elevated HbA1c levels have their elective surgery postponed until better glycemic control can be achieved.

Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.

Parthenolide is a naturally occurring terpene with promising anticancer properties, in particular in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50 values in the low micromolar range. These studies demonstrate that different O−H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 22a and 25b were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells.

Purpose: The aim of this work was to determine whether a commercial knowledge-based treatment planning (KBP) module can efficiently produce IMRT and VMAT plans in the pelvic region (prostate & cervical cancer), and to assess sensitivity of plan quality to training data and model parameters. Methods: Initial benchmarking of KBP was performed using prostate cancer cases. Structures and dose distributions from 40 patients previously treated using a 5-field IMRT technique were used for model training. Two types of model were created: one excluded statistical outliers (as identified by RapidPlan guidelines) and the other had no exclusions. A separate model for cervix uteri cancer cases was subsequently developed using 37 clinical patients treated for cervical cancer using RapidArcTM VMAT, with no exclusions. The resulting models were then used to generate plans for ten patients from each patient group who had not been included in the modelling process. Comparisons of generated RapidPlans with the corresponding clinical plans were carried out to indicate the required modifications to the models. Model parameters were then iteratively adjusted until plan quality converged with that obtained by experienced planners without KBP. Results: Initial automated model generation settings led to poor conformity, coverage and efficiency compared to clinical plans. Therefore a number of changes to the initial KBP models were required. Before model optimisation, it was found that the PTV coverage was slightly reduced in the superior and inferior directions for RapidPlan compared with clinical plans and therefore PTV parameters were adjusted to improve coverage. OAR doses were similar for both RapidPlan and clinical plans (p > 0.05). Excluding outliers had little effect on plan quality (p 0.05). Manually fixing key optimisation objectives enabled production of clinically acceptable treatment plans without further planner intervention for 9 of 10 prostate test patients and all 10 cervix test patients. Conclusions: The Varian RapidPlanTM system was able to produce IMRT & VMAT treatment plans in the pelvis, in a single optimisation, that had comparable sparing and comparable or better conformity than the original clinically acceptable plans. The system allows for better consistency and efficiency in the treatment planning process and has therefore been adopted clinically within our institute with over 100 patients treated.

Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36(+) LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.

Electron paramagnetic resonance (EPR) is one of the few methods that allows for the unambiguous detection of nitric oxide (NO). However, the dithiocarbamate-iron spin traps employed with this method inhibit the activity of nitric oxide synthase and catalyze NO production from nitrite. These disadvantages limit EPR's application to biological NO detection. We present a liposome-encapsulated spin-trap (LEST) method for the capture and in situ detection of NO by EPR. The method shows a linear response for [NO]≥4 µM and can detect [NO]≥40 nM in a 500 µL sample (≥20 pmol). The kinetics of NO production can be followed in real time over minutes to hours. LEST does not inhibit the activity of inducible nitric oxide synthase or nitrate reductase and shows minimal abiotic NO production in the presence of nitrite and NADH. Nitrate reductase-like activity is detected in cell lysates of the coccolithophore Emiliania huxleyi and is elevated in virus-infected culture. This method shows particular promise for NO detection in cell lysates and crude preparations of NO-producing tissues.

Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against pre-leukemic clonal expansion. Acute exposure to the pro-inflammatory cytokine interleukin (IL)-1 drives myeloid cell production and HSC cell cycle entry. However, HSC return to a quiescent state suggesting the presence of a ‘braking’ mechanism that limits HSC proliferative capacity during chronic inflammation. To identify mechanism(s) regulating HSC cell cycle activity, we injected mice with IL-1 for 20 days modeling chronic inflammation in vivo. RNA-seq analysis of HSC following IL-1 exposure revealed repression of cell cycle and protein synthesis genes, suggesting the activation of a ‘growth arrest’ gene program. This gene program coincided with increased PU.1 expression, and ChIP-seq analysis identified PU.1 binding on nearly all repressed genes, suggesting PU.1 enforces HSC quiescence during chronic inflammation. Strikingly, HSC from IL-1 treated PU.1-deficient mice exhibited loss of quiescence associated with aberrant myeloid expansion in the bone marrow and spleen. Together, our results suggest PU.1 induction maintains HSC quiescence under chronic inflammatory stress. They also suggest IL-1 may confer a competitive advantage to HSC with impaired PU.1 function, triggering aberrant proliferation and myeloid expansion. Several oncogenic mutations found in acute myelogenous leukemia (AML) impair the expression and/or function of PU.1. As AML pre-dominantly affects elderly individuals and leukemogenesis is often associated with chronic inflammation, our data supports a model where chronic inflammation triggers the selective expansion of HSC harboring oncogenic mutations, leading to a pre-leukemic state. Thus, blockade of inflammation may be a tractable approach to delay and/or prevent leukemia.

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Pregnant women, postpartum women, and infants are at high risk for complications from influenza. From October to November 2012, Text4baby, a free national text service for pregnant women and mothers of infants aged1 year, implemented a module of interactive messages encouraging maternal influenza vaccination. A program evaluation examined whether a text-based reminder or tailored education improved self-reported influenza vaccination or intent to be vaccinated later in the influenza season among Text4baby participants.Nearly one third (28,609/89,792) of enrollees responded to a text asking about their vaccination plans. Those planning to receive vaccination were randomly assigned to receive an encouragement message or an encouragement message plus the opportunity to schedule a reminder (n=3,021 at follow-up). Those not planning to be vaccinated were randomly assigned to receive general education or education tailored to their reason for non-vaccination (n=3,820 at follow-up). The effect of the enhanced messages was assessed using multinomial logistic regression in 2013-2014.A reminder increased the odds of vaccination at follow-up among mothers (AOR=2.0, 95% CI=1.4, 2.9) and of continued intent to be vaccinated later in the season (pregnant, AOR=2.1, 95% CI=1.4, 3.1; mother, AOR=1.7, 95% CI=1.1, 2.5). Among mothers not planning to be vaccinated because of cost, those who received a tailored message about low-cost vaccination had higher odds of vaccination at follow-up (AOR=1.9, 95% CI=1.1, 3.5). Other tailored messages were not effective.Text reminders and tailored education may encourage influenza vaccination among this vulnerable population; both have now been incorporated into Text4baby.

Tangible evidence of Earth's earliest (Hadean; >4.0 Ga) crust, and the processes and materials that contributed to its formation, exists almost entirely in a record of detrital zircon from Jack Hills, Western Australia, and a few other locations. Iceland, with its thick, juvenile, basaltic crust and relatively abundant silicic rocks, is considered a potential modern analog for the Hadean magmatic environment where >4 Ga zircon formed. We present the first extensive dataset for Icelandic zircon, with trace element and oxygen isotope compositions from samples that span the island's history and full range of tectonic settings. This statistically robust zircon-based comparison between Iceland and the early Earth reveals distinctions in chemistry that suggest fundamental differences in magmatic environments. Whereas the δ18O signature of Hadean zircons generally exceed that of zircons equilibrated with mantle-derived magma ( 85 % ≥ 5.3 ‰ ; median 6‰), almost all Icelandic zircons are characterized by a “light” oxygen signature ( 98 % ≤ 5.3 ‰ ; median 3‰). Deviations from “juvenile” oxygen values indicate that many Hadean zircons and almost all Icelandic zircons grew from magmas with substantial contributions from materials that had interacted with surface waters. In the Hadean case, the interaction occurred at low temperatures, while in Iceland, it was a high-temperature interaction. Icelandic and Hadean zircons are also distinct in their Ti concentrations (Icelandic median concentration 12 ppm, Hadean median 5 ppm). Titanium in zircon correlates positively with temperature of crystallization, and this difference in median Ti concentration suggests a temperature difference of at least 50 °C. Other differences in trace elements compositions are consistent with the interpretation that Icelandic and Hadean zircons grew in magmas with very different origins and histories (e.g., the heavy rare earth element Yb is almost an order of magnitude higher in Icelandic zircon). A comparison with elemental data for Phanerozoic zircon from different environments demonstrates that the Hadean population is unusually depleted in Ti, but otherwise similar to zircons from continental arc settings. Zircons from Iceland, and from modern evolving rift environments where oceanic lithosphere and upwelling asthenosphere are replacing continental lithosphere, are compositionally intermediate between mid-ocean ridge and continental arc zircon populations. The elemental distinctions are consistent with fractionation of zircon-bearing magmas under hotter and drier conditions in Icelandic, mid-ocean ridge, and evolving rift environments and cooler and wetter conditions in arc and, especially, Hadean environments.

Glass beads are a novel TL dosimeter in radiotherapy. An important characteristic of TL dosimeters is their energy response, especially when intended for use in radiotherapy applications over a wide range of energies (typically from X-rays generated at 80 kVp up to 25 MV photon and MeV electron beams). In this paper, the energy response of glass beads (Mill Hill, Japan) is investigated for their TL response to kV X-rays from an orthovoltage radiotherapy unit and also for MV photon and MeV electron beams from a medical linear accelerator. The experimental findings show that for photon and electron beams, the TL response of this particular glass bead, normalised to unity for 6 MV X-rays (TPR20/10¼0.670), decreases to 0.9670.02 for 15 MV X-rays (TPR20/10¼0.761) and to 0.9570.01 for 20 MeV electron beams (R50,D¼8.35 cm). This compares favourably with other TLD materials such as LiF and also alanine dosimeters that are readout with an EPR system. For kV X-rays, the response increases to 4.5270.05 for 80 kV X-rays (HVL¼2.4 mm Al) which approaches 3 times that of LiF TLDs and 5 times that of alanine. In conclusion, the particular glass beads, when used as a dosimeter material, show a relatively small energy dependence over the megavoltage range of clinically relevant radiation qualities, being clearly advantageous for accurate dosimetry. Conversely, the energy response is significant for photon beam energies covering the kV range. In both circumstances, in dosimetric evaluations the energy response needs to be taken into account.

Recent developments in advanced radiotherapy techniques using small field photon beams, require small detectors to determine the delivered dose in steep dose gradient fields. Commercially available glass jewellery beads exhibit thermoluminescent properties and have the potential to be used as dosimeters in radiotherapy due to their small size (

Myelodysplastic syndrome (MDS) is a group of heterogeneous disorders caused by ineffective hematopoiesis and characterized by bone marrow dysplasia and cytopenia. Current treatment options for MDS are limited to supportive care, hypomethylating agents, and stem cell transplant. Most patients eventually succumb to the disease or progress to leukemia. Previously, we found that CD123 can be used to delineate MDS stem cells in patients at high risk for MDS and that the CD123-positive population is biologically distinct from normal hematopoietic stem cells. Furthermore, selective targeting of MDS stem cells can dramatically reduce tumor burden in preclinical models. On the basis of these findings, we propose CD123 as a candidate target for chimeric antigen receptor (CAR) T-cell therapy in high-risk MDS patients. To test this concept, we employed a CAR lentiviral vector containing a CD123-specific single-chain variable fragment in combination with the CD28 costimulatory domain, CD3ζ signaling domain, and truncated estimated glomerular filtration rate. Utilizing this system, we illustrate that CD123 CAR can be expressed on both healthy donor and MDS patient-derived T lymphocytes with high efficiency, leading to the successful elimination of MDS stem cells both in vitro and in patient-derived xenografts. These results provide the concept for the use of CD123-targeted CAR T cells as a therapeutic option for patients with MDS.

SUMMARY The NADPH-dependent oxidase NOX2 is an important effector of immune cell function, and its activity has been linked to oncogenic signaling. Here, we describe a role for NOX2 in leukemia-initiating stem cell populations (LSCs). In a murine model of leukemia, suppression of NOX2 impaired core metabolism, attenuated disease development, and depleted functionally defined LSCs. Transcriptional analysis of purified LSCs revealed that deficiency of NOX2 collapses the self-renewal program and activates inflammatory and myeloid-differentiation-associated programs. Downstream of NOX2, we identified the forkhead transcription factor FOXC1 as a mediator of the phenotype. Notably, suppression of NOX2 or FOXC1 led to marked differentiation of leukemic blasts. In xenotransplantation models of primary human myeloid leukemia, suppression of either NOX2 or FOXC1 significantly attenuated disease development. Collectively, these findings position NOX2 as a critical regulator of malignant hematopoiesis and highlight the clinical potential of inhibiting NOX2 as a means to target LSCs., Graphical Abstract, In Brief The NADPH-dependent oxidase NOX2 is important for normal myeloid cell function. Adane et al. show that NOX2 is expressed in leukemic stem cells, where it regulates the balance of myeloid differentiation and self-renewal. Deficiency of NOX2 altered core metabolism, exacerbated inflammatory signaling, and limited in vivo disease development.

Submarine mass failures (which include submarine slides or submarine landslides) occur widely on open continental margins. Understanding their cause is of great importance in view of the danger that they can pose both to coastal populations through tsunamis and to the exploitation of ocean floor resources through mass movement of the sea floor. Present knowledge of the causes of submarine mass failures is briefly reviewed, focussing on the role of sea level rise, a process which has previously only infrequently been cited as a cause. It is argued that sea level rise could easily have been involved in at least some of these events by contributing to increased overpressure in sediments of the continental margin whilst causing seismic activity. The Holocene Storegga Slide off South West Norway may have been partly caused by the early Holocene sea level rise in the area, accentuated by meltwater flux from the discharges of Lake Agassiz–Ojibway in North America. Relative sea level rise increased water loading on the Norwegian continental margin, increasing overpressure in the sediments and also causing seismic activity, triggering the Holocene Storegga Slide. Given that some forecasts of future sea level rise are not greatly different from rises which obtained during the early Holocene, the implications of rising sea levels for submarine mass failures in a global warming world are considered.

A phase I study utilizing decitabine (DAC) followed by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, in patients with relapsed/refractory adult AML was undertaken to assess safety and feasibility. Patients received DAC 20mg/m(2) intravenously daily for 5 days followed by rapamycin from day 6 to day 25 at doses of 2 mg, 4 mg, and 6 mg/day in a standard 3+3 dose escalation design. Twelve patients completed treatment for safety evaluation. Maximum tolerated dose (MTD) was not reached, and except for grade 3 mucositis in 4 patients, no other significant unexpected non-hematologic toxicities have occurred indicating safety of this regimen. This trial is registered at clinical trials.gov as NCT00861874.

The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells.

SummaryWe used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.

The clinical academic practice partnership (CAPP), a clinical redesign based on the dedicated education unit concept, was developed and implemented by large, private school of nursing in collaboration with 4 clinical partners to provide quality clinical education, to explore new clinical models for the future, and to test an innovative clinical education design. An executive steering committee consisting of nursing leaders and educators from the school of nursing and the clinical institutions was established as the decision-making and planning components, with several collaborative task forces initiated to conduct the work and to accomplish the goals. This article will describe methods to initiate and to organize the key elements of this dedicated education unit-type clinical model, providing examples and an overview of the steps and elements needed as the development proceeded. After 18 months of implementation in 4 different nursing programs in 4 different clinical institutions, the clinical redesign has shown to be a positive initiative, with students actively requesting CAPP units for their clinical experiences. Preliminary findings and outcomes will be discussed, along with nursing education implications for this new clinical redesign.

Fluorine-18-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET)-guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to (18)F-FDG-PET-positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gy in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI(Paddick)) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI(Paddick) scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8-49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). (18)F-FDG-PET-guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.

There are a number of approaches for selective targeting of leukemic stem cells (LSCs). These include targeting stem-cell properties, such as self-renewal, inducing cycling of quiescent LSCs to sensitize them to conventional agents, employing or inducing immune-based mechanisms, and targeting tumor-specific physiology. Agents such as parthenolide inhibit the ability of leukemic stem cells to respond to oxidative stress and make leukemic stem cells and bulk leukemic cells susceptible to cell death, while normal stem cells remain relatively unharmed by these agents. The major mechanism of action of these small molecules appears to revolve around the aberrant glutathione metabolism pathway found in leukemic cells.

Temporal and spatial patterns of relative sea level (RSL) change in the North of Britain and Ireland during the Holocene are examined. Four episodes, each defined by marked changes in the RSL trend, are identified. Each episode is marked by a rise to a culminating shoreline followed by a fall. Episode HRSL-1 dates from the Younger Dryas to early in the Holocene; HRSL-2 to HRSL-4 occurred later in the Holocene. There is extensive evidence for each episode, and on this basis the spatial distribution of the altitude data for three culminating shorelines and a shoreline formed at the time of the Holocene Storegga Slide tsunami (ca 8110 ± 100 cal. BP) is analysed. Ordinary Kriging is used to determine the general pattern, following which Gaussian Trend Surface Analysis is employed. Recognising that empirical measurements of RSL change can be unevenly distributed spatially, a new approach is introduced which enables the developing pattern to be identified. The patterns for the most widely occurring shorelines were analysed and found to be similar and common centre and axis models were developed for all shorelines. The analyses described provide models of the spatial pattern of Holocene RSL change in the area between ca 8100 cal. BP and ca 1000 cal. BP based on 2262 high resolution shoreline altitude measurements. These models fit the data closely, no shoreline altitude measurement lying more than −1.70 m or +1.82 m from the predicted value. The models disclose a similar pattern to a recently published Glacial Isostatic Adjustment model for present RSL change across the area, indicating that the overall spatial pattern of RSL change may not have varied greatly during the last ca 8000 years.

SummaryLeukemia stem cells (LSCs) represent a biologically distinct subpopulation of myeloid leukemias, with reduced cell cycle activity and increased resistance to therapeutic challenge. To better characterize key properties of LSCs, we employed a strategy based on identification of genes synergistically dysregulated by cooperating oncogenes. We hypothesized that such genes, termed “cooperation response genes” (CRGs), would represent regulators of LSC growth and survival. Using both a primary mouse model and human leukemia specimens, we show that CRGs comprise genes previously undescribed in leukemia pathogenesis in which multiple pathways modulate the biology of LSCs. In addition, our findings demonstrate that the CRG expression profile can be used as a drug discovery tool for identification of compounds that selectively target the LSC population. We conclude that CRG-based analyses provide a powerful means to characterize the basic biology of LSCs as well as to identify improved methods for therapeutic targeting.

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

Titanium dioxide is one of the most commonly used semiconductors for photocatalytic applications. In the majority of experimental studies, titanium dioxide is used in a powder form. In the present investigations titanium dioxide layers were formed by the plasma assisted anodic oxidation process SOLECTRO®. In this process a titanium substrate (anode) is dipped into an electrolyte bath containing a titanium precursor. Impressing a voltage greater than 100 V, a titanium dioxide layer is deposited on the substrate in several minutes. The titanium dioxide is formed from the constituents of the electrolyte. For this reason, the composition of the electrolyte influences the deposition process and also the phase fractions and the layer morphology. It is known that the photocatalytic activity of titanium dioxide layers depends strongly on the anatase volume fraction, the layer morphology and therefore the specific surface area. The standard SOLECTRO® process generates titanium dioxide layers consisting of nearly 25 vol.% anatase and 75 vol.% rutile. In the present study, the electrolyte's constituents, especially the chelating agent, were varied to increase the anatase percentage. The results show that the anatase fraction and the specific surface area can be increased by substitution of ethylendiammintetraacetic acid by dieethylenetriaminepentaacetic acid. The anatase fraction amounts to 44 vol.% using the new electrolyte composition.