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Despite the growing number of studies of imagery and the use of complementary and alternative modalities as treatments for asthma, research on mental imagery in adults with asthma is practically, nonexistent. The purpose of this feasibility study was to lay groundwork for a larger follow-up clinical trial. To determine whether pulmonary function, asthma symptoms, quality of life, depression, anxiety, and power differ over time in adults with asthma who do and do not practice mental imagery (MI). (Power is the ability to make aware choices with the intention of freely involving oneself in creating desired change.) Randomized controlled study using univariate repeated measures analysis of variance (ANOVA) and replacement through block design. Lenox Hill Hospital, an affiliate of New York University Medical School, New York, NY. Sixty-eight adults with symptomatic asthma, after 4 weeks of baseline data collection and analysis, met requirements for this randomized controlled study. Thirty-three completed pulmonary function as well as self-report tests at 4 time points over 17 weeks. The 16 experimental participants also completed the 4-session imagery protocol. Individual imagery instruction (week 1) and follow-up (weeks 4, 9, 15). Participants were given 7 imagery exercises to select from and practice 3 times a day for a total of 15 minutes. 1) Spirometry (FEV1); 2) medication use; 3) Asthma Quality of Life Questionnaire; 4) Beck Depression Inventory; 5) Spielberger Anxiety Scales (A-State and A-Trait); 6) Barrett Power as Knowing Participation in Change Tool, Version II; 7) Epstein Balloon Test of Ability to Image. There was little evidence of statistical change in this feasibility study; yet, valuable lessons were learned. Paired t-tests indicated there was a significant difference in the total power scores in the imagery group, and in the expected direction (two-tailed, t-statistic = -2.3, P = 0.035) and the choices sub-scale (two-tailed, tstatistic = -2.93, P = 0.01) of the power instrument from weeks one to 16 of the study. Eight of 17 (47%) participants in the MI group reduced or discontinued their medications. Three of 16 (19%) participants in the control group reduced their medications; none discontinued. Chi-square indicated differences between groups (X2 = 4.66, P = 0.05). Persons who reduced or discontinued their medications showed neither an increase in pulmonary function prior to medication discontinuation, nor a fall in these parameters following discontinuation. Findings related to major outcome measures must be viewed with caution due to the small sample size resulting from attrition related to labor intensiveness and, therefore, low statistical power. However, the study did provide significant data to plan a larger scale study of the use of mental imagery with adult asthmatics. The study also demonstrated that imagery is inexpensive, safe and, with training, can be used as an adjunct therapy by patients themselves. Its efficacy needs additional exploration. Further research for adults with asthma who practice imagery is important, as current treatments are not entirely efficacious. Lessons learned in this study may facilitate improvement in research designs.

That came later. I didn't pursue [Abba] for their permission until we had the money. Then they said no. And we found out that Abba had never licensed their music to anyone else. We sent them a screenplay with a letter begging them to read it. We got a message from their assistant saying: 'They won't read it, and even if they did, it would still be \"No\".' So Lynda House (producer) asked the assistant to read it, and she did, and she loved it. So she said: 'Look, I don't know if I can promise you anything because they have never said yes, but I'll tell you what to do. Keep up the flattering letters.' So I did, and she got them to read the screenplay. They liked it. But they still said no. We just kept at them. I would send them a letter once a week. And I was shameless. I compared them to the Beatles. I think I called them good looking. Finally I said to Lynda: 'I can't replace them. I'm going to fly to Sweden and hang out on their doorstep till they say yes to me.' Lynda said: 'Before we do that, let's warn them that you are coming so that they're there.' She sent them a photocopy of my air ticket and they said yes. I had to have Abba. What would the film have been without Abba? It's [Muriel]'s music! We cast for a very long time. We started looking very early, before pre-production. We all knew it was going to be hard to cast Muriel. I think I saw every young actress in Australia. Toni Collette had had a lot of difficulty getting work because she didn't look like everybody else. When she came in I thought she's really good but I wasn't sure she was right. And I went on looking for Muriel for another month. I think I needed to see all these other people to prove that it was her. Toni desperately wanted the role and I was asking a great deal. I wanted an actress who was ready to gain weight because I knew there was going to be a scene where she was dressed in a white satin pant suit and you couldn't fake her thighs. And Toni was willing to do it. She said: 'I'll be paid to gain weight for this. That will make it a pleasure.' But I don't think she found it a pleasure in the end. I always say that with Muriel I became a director whose next film was anticipated rather than feared. It changed everything. And the moment it changed was the night it screened at Cannes. It just went through the roof. The audience were screaming and clapping, it got a 15-minute standing ovation. Toni Collette was with me; and she had lost all the weight she'd put on for the film. Her dream, she told me, was that she would appear at Cannes, thin. I went on stage first and then Toni came on. And for a moment you could tell the audience didn't know who she was. And then when they recognised her, the applause just went on and on.

I hadn't stayed long enough to learn any technical knowledge at Vancouver. Thankfully [Scott Mosier] and [David Klein] had, so David handled the camera and Scott operated the sound. Periodically David would set up the frame and ask, 'What do you think of this?' And I'd look through the lens and go, 'It looks wonderful.' Originally, I had wanted to shoot in colour, but Scott told me that we would have to rent an entire light package. If we shot in black and white we could use the store's fluorescent lights. Scott and I worked in the convenience store and the video store during the entire shoot. I would work the six till 11am shift. From 11 to five we were either sleeping or preparing for the next night's shooting. From five or six till 10.30 at night I was working again. Then from 10.30 till six in the morning we would shoot the movie. And then the day would begin again. Sometimes we would end a little earlier than 6am and we would go and sleep next door in the video store. We had pillows and some blankets and went and slept on the floor in the video store. We brought an editing unit into the video store so we could film and edit simultaneously. Scott would edit while I worked in the convenience store and vice versa. We had four successful screenings. It was the first time we saw the movie with a full audience and to hear the cacophonous laughter, the roaring, was a deeply satisfying feeling. But still no distributors were interested in buying the film. Then Harvey Weinstein saw it and loved it. [John Pierson] arranged a meeting with Harvey. He said, 'You made a fucking funny movie. I'll take it and put it on a bunch of fucking screens, show it to the right fucking people, put a fucking soundtrack in there' Scott and I were impressed. He was our kind of guy: very blunt and very frank. So he made us an offer. The sum was very low, only $227,000. Twenty-seven grand would cover the hard cost of the movie, not the interest on the credit cards. And then we were left with a $100,000 to split between us and all the people on the cast. John said: 'We could really push for more cash but is this how you want to enter into a relationship with these people? This way we go in low. If the movie breaks out they will love you for the rest of your lives.' The movie eventually made about $8 million worldwide and we have stayed with Miramax ever since.

Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma-bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma-bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8+ T cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15  months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.