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From the mid-1950s through the 1960s, Hungarian composer Gyèorgy Ligeti went through a remarkable period of stylistic transition, from the emulation of his fellow countryman Bâela Bartâok to his own individual style at the forefront of the Western-European avant-garde. Through careful study of the sketches and drafts, as well as analysis of the finished scores, Metamorphosis in Music takes a detailed look at this compositional evolution. Author Benjamin R. Levy includes sketch studies created through transcriptions and reproductions of archival material-much of which has never before been published-providing new, detailed information about Ligeti's creative process and compositional methods. The book examines all of Ligeti's compositions from 1956 to 1970, analyzing little-known and unpublished works in addition to recognized masterpieces such as Atmospháeres, Aventures, the Requieim, and the Chamber Concerto. Discoveries from Ligeti's sketches, prose, and finished scores lead to an enriched appreciation of these already multifaceted works.

Remembering and forgetting reflect fundamentally interdependent processes in human memory (Bjork, 2011 ). This interdependency is particularly apparent in research on retrieval-induced forgetting, which has shown that retrieving a subset of information can cause the forgetting of other information (Anderson et al. Journal of Experimental Psychology: Learning, Memory, & Cognition 20:1063-1087, 1994 ). According to one prominent theoretical account, retrieval-induced forgetting is caused by an inhibitory process that acts to resolve competition during retrieval. Specifically, when cues activate competing, contextually inappropriate responses, those responses are claimed to be inhibited in order to facilitate the retrieval of target responses (Anderson Journal of Memory and Language 49: 415–445, 2003 ; Levy & Anderson Trends in Cognitive Sciences 6: 299–305, 2002 ; Storm, 2011b ). Interest in retrieval-induced forgetting has grown steadily over the past two decades. In fact, a search of the abstracts at the 5th International Conference on Memory (ICOM, York University, 2011) revealed 40 presentations specifically mentioning “retrieval-induced forgetting,” and nearly twice that number referring to the concept of inhibition. Clearly, researchers are interested in the empirical phenomenon of retrieval-induced forgetting, and inhibition is gaining increasing attention as a mechanism involved in memory. The goal of the present progress report is to critically review the inhibitory account of retrieval-induced forgetting and to provide direction so that future research can have a more meaningful impact on our understanding of human memory.

Circulating cell-free tumor DNA (ctDNA) can serve as a real-time biomarker of tumor burden and provide unique insights into the evolving molecular landscape of cancers under the selective pressure of immunotherapy. Tracking the landscape of genomic alterations detected in ctDNA may reveal the clonal architecture of the metastatic cascade and thus improve our understanding of the molecular wiring of therapeutic responses. While liquid biopsies may provide a rapid and accurate evaluation of tumor burden dynamics during immunotherapy, the complexity of antitumor immune responses is not fully captured through single-feature ctDNA analyses. This underscores a need for integrative studies modeling the tumor and the immune compartment to understand the kinetics of tumor clearance in association with the quality of antitumor immune responses. Clinical applications of ctDNA testing in patients treated with immune checkpoint inhibitors have shown both predictive and prognostic value through the detection of genomic biomarkers, such as tumor mutational burden and microsatellite instability, as well as allowing for real-time monitoring of circulating tumor burden and the assessment of early on-therapy responses. These efforts highlight the emerging role of liquid biopsies in selecting patients for cancer immunotherapy, monitoring therapeutic efficacy, determining the optimal duration of treatment and ultimately guiding treatment selection and sequencing. The clinical translation of liquid biopsies is propelled by the increasing number of ctDNA-directed interventional clinical trials in the immuno-oncology space, signifying a critical step towards implementation of liquid biopsies in precision immuno-oncology.

Discussing his Horn Trio, György Ligeti imaginatively describes the second movement as a dance that was “inspired by different folk musics of nonexistent people, as if Hungary, Romania, and all of the Balkans were located somewhere between Africa and the Caribbean.” And in more general remarks about his works, he goes on to suggest that, rather than overtly referencing their stylistic features, he abstracted technical principles from various traditions and combined them into an idiosyncratically amalgamated musical language. This essay shows an expansive approach to hybridity in Ligeti's Violin Concerto and Hamburg Concerto , going well beyond previous remarks about African rhythmic influences. Ligeti's practice encompasses not only rhythm, but also texture, pitch, and tuning systems; it spans a wider breadth of traditions as well, including newly identified sources such as flute and panpipe ensembles from New Guinea and yodeling traditions from across the globe. An analysis of passages from these late concertos – undertaken alongside evidence from his ethnomusicological sources, recordings, and sketches housed at the Paul Sacher Stiftung – demonstrates the intricacies and patterns of Ligeti's late style and the compelling statement it makes about the role of hybridity and globalization in contemporary life.

When reminded of something we would prefer not to think about, we often try to exclude the unwanted memory from awareness. Recent research indicates that people control unwanted memories by stopping memory retrieval, using mechanisms similar to those used to stop reflexive motor responses. Controlling unwanted memories is implemented by the lateral prefrontal cortex, which acts to reduce activity in the hippocampus, thereby impairing retention of those memories. Individual differences in the efficacy of these systems may underlie variation in how well people control intrusive memories and adapt in the aftermath of trauma. This research supports the existence of an active forgetting process and establishes a neurocognitive model for inquiry into motivated forgetting.

BackgroundDespite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor–immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade.MethodsUsing machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance.ResultsIntegrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts.ConclusionsOur findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.

Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb.

Summary Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in a range of affective and stress-related disorders. The regulatory systems that control HPA activity are subject to modulation by environmental influences, and stressful life events or circumstances can promote subsequent HPA dysregulation. The brain is a major regulator of the HPA axis, and stress-induced plasticity of the neural circuitry involved in HPA regulation might constitute an etiological link between stress and the development of HPA dysregulation. This review focuses on the synaptic regulation of neuroendocrine corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which are the cells through which the brain predominantly exerts its influence on the HPA axis. CRH neuronal activity is largely orchestrated by three neurotransmitters: GABA, glutamate, and norepinephrine. We discuss our current understanding of the neural circuitry through which these neurotransmitters regulate CRH cell activity, as well as the plastic changes in this circuitry induced by acute and chronic stress and the resultant changes in HPA function.

The “microbiome” is colloquially taken to mean the relative abundance of the genera and species that constitute the gut bacteria (“taxonomy”); however, the microbiome in its broadest sense encompasses bacterial taxonomy, gut fungi (“mycobiome”) and viruses (“virome”), and the totality of their functional and metabolic state (2,5,6). Any agent that modifies this ecology can be considered an MBT. [...]we believe that an MBT used for therapeutic intent to treat specific human diseases should be regulated by the US FDA and require an IND before clinical trial. Author Notes Correspondence: Shrinivas Bishu, MD. Email: bishus@med.umich.edu REFERENCES 1.Fan, Y, Pedersen, O. Gut microbiota in human metabolic health and disease.