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This chapter examines the life and art of Polish-born Jewish actor and dancer Felix Fibich as a rich example of the intersection of discourses about the Jewish body, movement, the emotions, and dance in the twentieth century. Fibich devoted his life to performing, analyzing, and preserving “Jewish movement,” which he believed was the direct reflection of a unique Jewish character. The chapter demonstrates how the specific image and enactment of the torqued, angular body, defined by twists and oppositional pulls in space, provides a powerful modernist mapping of Jewish male subjectivity that migrated from Eastern Europe to the United States, and also of the struggle for transcendence in the face of adversity. Frequently represented in popular culture in a simplistic and stereotyped manner, this richly conceived perspective of the dancing Jewish body provides important insights into shifting ideas about the relationship between Jewish souls, bodies, and emotions.

The introduction begins with an overview of the foundations of the academic field of Jewish dance studies. It is meant to acknowledge the incredible work that has been done to 2020 and demonstrate how these efforts inform the Handbook. As part of this discussion an important shift is documented in conceptualizing (and languaging) the field from its inception to the date of publication. Providing the larger contextual frame is critical for understanding the conceptual orientation of the volume. Drawing on this history, the choice of the term “Jewishness” in the title, rather than Judaism or other terminology related to specific Jewish traditions (such as Israeli, Yemenite, Yiddish, and so on), is then explained. The historical record also provides the means for delineating what areas are addressed in the Handbook as well as those that have already been well-covered and consequently not emphasized here. Next, we address the structure of the Handbook and an explanation for its tripartite organization. Finally, we look forward, considering what gaps and questions remain, and our hopes for the future of the field.

Pregnancy is a time of many physiologic and systemic changes that may predispose women to new neurologic diseases or alter the course of preexisting disease. Management of neurologic diseases during pregnancy is complicated by the risks and benefits to both mother and fetus that must be weighed when diagnostic tests and therapeutic options are selected.

OBJECTIVES: Determine the extent to which diets with higher fiber intakes (g) at baseline are independently associated with cancer development by final study visit in a cohort of rural post-menopausal women. METHODS: This study was a secondary analysis of participants in a four-year randomized controlled trial evaluating the effect of vitamin D and calcium supplementation (2000 IU/d vitamin D3 and 1500 mg/d calcium) on cancer development in rural post-menopausal women in Nebraska (June 2009-August 2015). Diets, including fiber intake (total, soluble, fruit-vegetable, grain and bean fiber), were evaluated via a 2005 Block Food Frequency Questionnaire at baseline. T-tests were used to evaluate the difference in dietary fiber intakes between all-type cancer and non-cancer groups. Logistic regression models, controlling for pertinent covariates, were used to determine if dietary fiber intake at baseline is associated with the cancer development. Dietary fiber variables were log-transformed and stratified by treatment group. RESULTS: There were 1977 participants available for analysis. Median total fiber intake was 14.35 g or 65% of the Dietary Reference Intake. There was no significant difference between dietary fiber intakes at baseline between the cancer group and non-cancer group. For people on vitamin D and calcium supplementation, higher dietary soluble fiber and fruit-vegetable fiber intakes at baseline were protective against cancer development [Soluble OR: 0.50; 95% CI (0.26, 0.96); Fruit-vegetable OR: 0.56; 95% CI (0.33, 0.94)]. In participants without vitamin D and calcium supplementation, the odds of having higher bean fiber intake was 1.62 times higher in those with cancer [OR: 1.62 (95% CI (1.07, 2.47)]. Total fiber and grain fiber intakes were not significantly associated with cancer development. CONCLUSIONS: While low fiber intake is prevalent among rural post-menopausal women, those with higher intakes of soluble and fruit-vegetable fiber may be more protected against development of all-type cancer when supplemented with calcium and vitamin D. Further analysis should examine the relationship between supplementation and bean fiber intake on the development of cancer. FUNDING SOURCES: The original study was funded by the National Cancer Institute and Creighton University internal funding. No additional funding was used for the secondary analysis.

The most common symptoms of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are fevers, fatigue and dry cough. However, growing data suggest gastrointestinal (GI) manifestations occur in the majority of patients. Small bowel obstruction remains a significant cause of surgical abdominal emergencies in the adult population, although most cases are secondary to adhesive disease. We present a case of ileocolonic intussusception in an adult with active COVID-19 infection. Our patient presented with small bowel obstruction 4 days after diagnosis of COVID-19 with typical respiratory symptoms. Imaging revealed ileocolonic intussusception and possible cecal mass for which a right hemicolectomy was performed. Recovery was unremarkable. Pathology suggested necrosis without an identifiable mass. To the best of our knowledge, this is the first documented case of small bowel obstruction secondary to ileocolonic intussusception in an adult related to GI manifestation of COVID-19.

Objectives To describe toxicity and tumor outcome after resection and aggressive re-irradiation (stereotactic radiosurgery(SRS) or brachytherapy) of brain metastasis that have pathologically confirmed recurrence after prior radiosurgery. Methods A retrospective chart review identified 40 lesions in 35 patients that were initially treated with SRS, then demonstrated evidence of recurrence with pathologic confirmation and underwent re-irradiation either with radiosurgery (n=28, 70%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 30%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of retreatment. Results Median follow-up from time of re-irradiation was 11.8 months (range 1 – 89.7 months). Dose for repeat radiosurgery was 18–25 Gy in 1–5 fractions, and brachytherapy dose was 55–65 Gy at 5 mm depth. Twelve lesions subsequently had imaging evidence of radionecrosis vs. progression. Of these, eight underwent repeat resection with pathology demonstrating radiation necrosis in five patients (n=4 with SRS, n=1 with brachy) and tumor recurrence in 3 (n=2 with brachy, and n=1 with SRS). Toxicities included: Steroids, 14(35%); imaging progression/necrosis 12(30%); grade 3/4 event, 3(20%); and surgically confirmed radionecrosis 5(12.5%). Local control of retreated lesions at 6 months is 85.5%, and at 12 months is 79.3%, OS at 1 year is 52.5% and at 2 years 46.6%. Local control at one year for repeat stereotactic treatment was 82.9% and for Cs131 brachytherapy was 80.8% Conclusions Aggressive re-irradiation after resection for pathologic confirmation appears to be appropriately safe and effective for the majority of patients after local failure of initial radiosurgery.

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

Brain metastasis is common in patients with breast cancer, and those with triple negative status have an even higher risk. Stereotactic radiosurgery (SRS) is preferred to whole brain radiation therapy (WBRT) in most patients. However, triple negative status is currently not considered when determining optimal radiation therapy. Given the aggressive nature of triple negative breast cancer, we evaluated a role for WBRT for all patients in this cohort. We conducted a single-institution retrospective cohort study to determine whether triple negative patients with brain metastases have a higher burden of intracranial disease and whether type of initial radiation therapy affects overall survival for this cohort of patients. 85 patients met the inclusion criteria for this study. 25% of patients had triple negative breast cancer, of which 91% received SRS and 53% of patients received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67 (St.Dev:1.1) in the non-triple negative status patients and 2.6 (St. Dev:3.7) in the triple negative status patients (p=0.001). Using a cox proportional hazards model, it was found that whole brain radiotherapy does not significantly affect overall survival in patients with triple negative breast cancer (p = 0.96). Our findings highlight the highly aggressive intracranial nature of triple negative breast cancer. Indeed, the rate of increase in brain metastases is significantly higher for triple negative patients compared to non-triple negative patients. As a result, we evaluated whether triple negative patients would benefit from whole brain radiation regardless of findings on initial brain imaging. Despite 53% of patients receiving WBRT, our investigation found that there is no additional benefit to WBRT in triple negative breast cancer patients. These results suggest a need to re-evaluate the role of WBRT in the management of triple negative breast cancer.

Inositol is a precursor for the phospholipid membrane component phosphatidylinositol (PI), involved in signal transduction pathways, endoplasmic reticulum stress, and osmoregulation. Alterations of inositol metabolism have been implicated in human reproductive issues, the therapeutic effects of drugs used to treat epilepsy and bipolar disorder, spinal cord defects, and diseases including diabetes and Alzheimer’s. The sole known inositol synthetic enzyme is myo-inositol synthase (MIPS), and the homolog in Drosophilia melanogaster is encoded by the Inos gene. Three identical deletion strains (inosΔDF/CyO) were constructed, confirmed by PCR and sequencing, and homozygotes (inosΔDF/inosΔDF) were shown to lack the transcript encoding the MIPS enzyme. Without inositol, homozygous inosΔDF deletion fertilized eggs develop only to the first-instar larval stage. When transferred as pupae to food without inositol, however, inosΔDF homozygotes die significantly sooner than wild-type flies. Even with dietary inositol the homozygous inosΔDF males are sterile. An inos allele, with a P-element inserted into the first intron, fails to complement this male sterile phenotype. An additional copy of the Inos gene inserted into another chromosome rescues all the phenotypes. These genetic and phenotypic analyses establish D. melanogaster as an excellent model organism in which to examine the role of inositol synthesis in development and reproduction.

Purpose To measure the value of early initial surveillance MRI scans in patients with brain metastases undergoing stereotactic radiosurgery (SRS), as MRI scans are a significant cost and patient stressor. Methods We identified a retrospective cohort of patients with brain metastases treated with SRS and followed at a single institution with scheduled 6-week or 12-week initial surveillance MRI. Imaging interval was based on policy of different providers. Outcome measures included new/progressive lesions, salvage treatment, detection of new lesions before symptoms, and use of surgical resection. Results Two hundred patients were included: 100 consecutive patients scanned with 6-week and 12-week imaging. Eighty-seven and 74 patients in each group had available follow-up imaging and were analyzed. Median time to MRI was 6.7 weeks and 13.5 (p1cm (20% vs 50%) when discovered. One patient in each group underwent surgical salvage. Conclusion While shorter 6-week interval MRI surveillance post-SRS may detect new/progressive disease less frequently than 12-week MRI surveillance intervals, short interval MRI may be more likely to detect new/progressive lesions before symptoms develop. Surgical salvage was uncommon with either schedule. Further study may identify a high-risk subgroup who would benefit from early surveillance.

There has been no focused study of the chorus in fourth-century drama. This may be, in part, explained by the difficult and diffuse evidence for its presence and activity. Two phenomena may also have discouraged scholars from attempting any such focused study: Aristotle’s castigation of later dramatic odes as embolima, and the replacement of choral odes in papyri with the mark χοροῦ‎, or χοροῦ μέλος‎—‘song of the chorus’. The notion that the chorus of drama in the fourth century was a pale shadow of its fifth-century self has flourished for well over a century. In order to do so, however, much positive evidence for the quantity and quality of the dramatic chorus has had to be explained away. An examination of the chorus itself, and the way contemporary thinkers used the idea of the chorus, will allow the re-writing of the history of Attic drama and its development.

As well as bringing together all the relevant evidence for the quality and activity of the chorus of drama in the fourth century, this monograph has raised certain key questions about the current understanding of the nature and development of Attic drama as a whole. First, it shows that the supposed ‘civic’ quality of the chorus of drama is, in fact, an association loaned, inappropriately, from the genre of circular, ‘dithyrambic’, choral performance. Being attentive to the cultural differences between these two genres should prompt a further re-evaluation of how to read dramatic choruses more generally. Second, the way in which key fourth-century authors such as Plato and Xenophon use the image of the chorus to discuss the concept of leadership has profoundly shaped ways of construing choreia in ancient Greek drama, and the ancient Mediterranean more generally. Armed with this knowledge, it is possible to retell the story and history of the chorus in drama.

This chapter brings together known and possible fourth-century choral tragic texts, analysing and evaluating the chorus’ dramatic activity in the later Classical period. Beginning with the Rhesus once attributed to Euripides, it examines the innovations and dramatic potential of this tragedy’s chorus in performance. In particular it highlights the unique instances of a fragmented choral voice, a striking independence in the chorus’ character, and the use of separated strophic pairs for dramatic structure. There follows an evaluation of the possible fragments of fourth-century tragic choral speech or song, and closer consideration of three such fragments all incidentally linked to the tragedian Astydamas. In these fragments the chapter views further signs of activity, choral interaction with actors, and literary play. A final section introduces a comparison with lyric poetic composition in the fourth century, taking Philodamus’ Paean to Dionysus as an illuminating example of sophisticated and potent choral performance in the fourth century.

Chapter 1 brings together the evidence for when and where dramatic choruses danced in the fourth century, providing an historical base for the later discussions of fourth-century dramatic choral activity. After establishing the certain and likely locations for dramatic performances in Athens, Attica, and the wider ancient Mediterranean (and beyond), the chapter considers the question of who the choral performers were, and what their choral training might have involved. Through this focus on the choral performer, and the practicalities of producing so many dramatic productions in each year, the chapter can begin to draw together a new picture of choral industry in the fourth century, an industry that clearly had its roots in the fifth century. Considering the theory that ‘local’, ‘amateur’ choruses would be recruited for travelling groups of actors, it suggests that the evidence supports, instead, a class of skilled choral performers in line with the industry’s professionalizing turn.

The practice of revival and reperformance of drama in the fourth century, a practice illuminated by recent scholarship, allows for a recalibration of the view of fourth-century dramatic choral practice. Acknowledging the fifth-century plays (and their choruses) that were definitely and possibly revived in the fourth century instantly enriches the picture of fourth-century dramatic choral culture. As well as reviewing the significance of revivals for fourth-century dramatic culture more generally, this chapter considers the sections of tragic text (so-called ‘interpolations’) that seem to have been added to fifth-century plays for, it contends, fourth-century revivals. The reconfigured choruses of Euripides’ Iphigenia at Aulis and Aeschylus’ Seven Against Thebes, indicate what might have been possible and desirable for producers to change for revivals of these plays. The qualities of the additions here analysed add further evidence for varied and valued dramatic choruses in the later classical period.

This chapter and the next considers the ‘snapshot’ of choral performance (dramatic and non-dramatic) that is presented by Aeschines, Demosthenes, Xenophon, Plato, comic poets, and historians and other fourth-century artists and writers. This allows for the contextualization of the evidence for fourth-century dramatic choruses in the choral culture of the time, but it also allows the examination of the cultural weight and impact of alluding to ‘a chorus’ in the fourth century. Here the chapter focuses on the chorus’ close associations with festival and how those associations are used by individuals for literary and rhetorical effect. Special attention is paid to the ways in which choral imagery can be separated out from imagery celebrating and commemorating choregoi and, in doing so, the chapter displays how important it is to be sensitive to the tendency in the sources to blur the boundaries between chorus and individual.

The chorus is frequently used as an analogue for the dynamics between a leader and those who follow. Chapter 7 focuses on two early ‘political theorists’, Xenophon and Plato, and the way they often reach for the image of a chorus as a means to illustrate and elucidate their arguments about leadership and the ideal society. While Xenophon tends towards a practical application of the dynamics between leader and led, found in choral training and performance, Plato is shown to go much further in his delineation of these dynamics, and their proposed practical use in his construction of the ‘second-best city’ in his Laws. Plato’s peculiar picture of the chorus, as a place where individuals lose their rationality and give themselves over to a child-like, ductile state, suits his overall aims in his construction of the city of Magnesia, but, the chapter argues, necessitates a profoundly distorted picture of ancient choreia.

The Chorus of Drama in the Fourth Century BCE seeks to upend conventional thinking about the development of drama from the fifth to the fourth centuries. Set in the context of a theatre industry extending far beyond the confines of the City Dionysia and the city of Athens, the identity of choral performers and the significance of their contribution to the shape and meaning of drama in the later Classical period (c.400–323) as a whole is an intriguing and under-explored area of enquiry. Drawing together the fourth-century historical, material, dramatic, literary, and philosophical sources that attest to the activity and quality of dramatic choruses, the book provides a new way of talking and thinking about the choruses of drama after the deaths of Euripides and Sophocles. Having considered the positive evidence for dramatic choral activity, the book provides a radical rethinking of two oft-cited yet ill-understood phenomena that have traditionally supported the idea that the chorus of drama ‘declined’ in the fourth century: the inscription of χοροῦ μέλος‎ in papyri and manuscripts in place of fully written-out choral odes, and Aristotle’s invocation of embolima (Poetics 1456a25–32). The book goes on to explore how influential fourth-century authors such as Plato, Demosthenes, and Xenophon, as well as artistic representations of choruses on fourth-century monuments, have had an important role in shaping later scholars’ understanding of the dramatic chorus throughout the Classical period. The book’s conclusions, too, have implications for the broader story we wish to tell about Attic drama, and its most enigmatic and fundamental element, the chorus.

BACKGROUND Due to disease and/or treatment-related injury, such as hypothalamic, visual, and endocrine damage, quality of life (QoL) scores after childhood-onset Adamantinomatous Craniopharyngioma (ACP) are among the lowest of all pediatric brain tumors. Decision-making regarding management would be aided by more complete understanding of a patients likely QoL trajectory following intervention. METHODS We retrospectively analyzed caregiver and patient-reported QoL-instruments from the first 50 patients (ages 1–17 years at diagnosis) enrolled in the international Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium. Surveys included 205 pediatric-relevant questions and were completed at diagnosis, and 1- and 12-months following diagnosis. Using Multiple Correspondence Analysis (MCA), these categorical QoL surveys were interrogated to identify time-dependent patient subgroups. Additionally, custom deep learning classifiers were developed using Google’s TensorFlow framework. RESULTS By representing QoL data in the reduced dimensionality of MCA-space, we identified QoL subgroups that either improved or declined over time. We assessed differential trends in QoL responses to identify variables that were subgroup specific (Kolmogorov-Smirnov p-value < 0.1; n=20). Additionally, our optimized deep learning classifier achieved a mean 5-fold cross-validation area under precision-recall curve score > 0.99 when classifying QoL subgroups at 12 month follow-up, using only baseline data. CONCLUSIONs This work demonstrates the existence of time-dependent QoL-based ACP subgroups that can be inferred at time-of-diagnosis via machine learning analyses of baseline survey responses. The ability to predict an ACP patient’s QoL trajectory affords caregivers valuable information that can be leveraged to maximize that patient’s psychosocial state and therefore improve overall therapy.

The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.

Substance use is a developmental disorder, with clear age-graded trends reflecting initiation in adolescence, increased use through emerging adulthood, and a decline thereafter. A developmental framework places substance use behavior both within the context of normal development and in relation to the interplay between environmental and person-specific characteristics, where underlying risk may manifest as a substance use problem in the face of an enabling environment. Individuals have changing vulnerabilities to substance use and related problems that are due to chronological aging as well as attributable to the normative developmental tasks and role transitions that may serve as a turning point directing an individual toward or away from substance use. Against the backdrop of normative patterns are distinct developmental trajectories that are likely linked to different etiological pathways and that, through valid testing of developmental theory, can inform the content and timing of prevention programs targeted to reach high-risk subgroups.

Alcohol is the substance most commonly used by youth. Problematic alcohol use can be considered a developmental disorder, which typically has its origins in an individual’s genetic liability, temperament, and experiences in childhood and adolescence. To provide a context for the emergence of alcohol use in adolescence, this chapter briefly reviews biological substrates of risk that include genetic liability and processes of developmental maturation (e.g., puberty, brain development). The chapter then addresses the prevalence of alcohol use and alcohol-related problems in adolescence, trajectories of youth alcohol use, and internalizing and externalizing behavior pathways associated with adolescent alcohol use. Risk and protective factors influencing adolescent alcohol use are discussed as targets to guide developmentally informed prevention and intervention.

INTRODUCTION: Checkpoint molecules like programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) act as negative regulators of the immune system and can be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produces long-term survivors in a murine glioma model.1 However, tumor infiltrating lymphocytes can express multiple checkpoints (including TIM-3), and expression of ≥2 checkpoints corresponds to a more exhausted T cell phenotype.2 It was therefore hypothesized that the addition of a second checkpoint-blocking antibody could achieve additive or synergistic antitumor effects. METHODS: C57BL/6 mice were implanted with mouse glioma cell line GL261 transfected with luciferase and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1 + SRS, (6) anti-TIM-3 + SRS, (7) anti-PD-1 + anti-TIM-3, and (8) anti-PD-1 + anti-TIM-3 + SRS. Overall survival was measured. Brain, cervical lymph nodes, and peripheral blood were harvested on day 21 to assess immune activation. RESULTS: Survival benefits were observed with combined anti-TIM-3 antibody + SRS compared to anti-TIM-3 antibody alone with a median survival (MS) of 69 vs. 25 days and overall survival (OS) of 50% vs. 0%, respectively (p < 0.001 by log-rank Mantel-Cox). Dual blockade with anti-TIM-3 + anti-PD-1 antibody also improved survival compared to TIM-3 blockade alone, (MS of 100 vs. 25 days, OS 60% vs. 0%, respectively, p < 0.05). Notably, OS in the triple therapy group (anti-PD-1 + anti-TIM-3 + SRS) was 100% by day 100 (p < 0.05), a significant improvement compared to all other treatment arms. Flow cytometry of organs harvested on day 21 showed that compared to the dual therapy groups, mice treated with triple therapy had increased tumor infiltration by interferon-gamma+ (IFNg) and tumor necrosis factor-alpha+ (TNFa)-producing CD4+ T cells, as well as IFNg+ CD8+ lymphocytes. CONCLUSIONS: Combining anti-TIM-3 with anti-PD-1 and radiation was synergistic and conferred a significant survival benefit.

INTRODUCTION: Glioblastoma is the most malignant brain tumor and is characterized by resistance to current therapies. Multi-modal treatment holds potential for complete tumor eradication, however the combination of chemotherapy and immunotherapy has been avoided due to concerns over possible mutually excluding effects. Localized chemotherapy (LC) consisting of biodegradable polymers as the delivery system for the BCNU (BCNU-LC) is FDA approved while treatment with the anti-PD-1 monoclonal antibody (anti-PD-1-mAb) has shown promising early results in clinical trials. Here we report evidence of superior survival and a positive immunological profile resulting from the combination of BCNU-LC + anti-PD-1-mAb in an established murine glioblastoma model. RESULTS: Mice were treated with the following regimens: BCNU-LC + anti-PD-1-mAb, systemic-BCNU + anti-PD-1-mAb, BCNU-LC, systemic-BCNU, anti-PD-1-mAb, untreated. BCNU-LC + anti-PD-1-mAb treated mice showed improved survival compared to mice treated with monotherapies and exhibited enhanced tumor-specific immunity: flow-cytometric analysis of the lymphocytic, myeloid, and microglial compartments in the tumor microenvironment as well as the lymphocytic and myeloid compartments in the periphery showed activation of immune molecules, whereas the mice treated with systemic-BCNU or systemic-BCNU + anti-PD-1-mAb exhibited severe immunosuppression in addition to poor survival. 70% of the BCNU-LC + anti-PD-1-mAb group exhibited long-term survival while the anti-PD-1-mAb, systemic-BCNU and systemic-BCNU + anti-PD-1-mAb groups also produced lower percentages of long-term survivors. Upon tumor re-challenge in the flank or the contralateral brain hemisphere, long-term survivors in the BCNU-LC + anti-PD-1-mAb and anti-PD-1-mAb groups were able to prevent formation of recurrence whereas long-term survivors from the systemic-BCNU and systemic-BCNU + anti-PD-1-mAb groups succumbed to Glioblastoma and were unable to form an immune memory response. CONCLUSIONS: Our results suggest that we rethink our chemotherapy strategies in the setting of immunotherapy. We found that systemic chemotherapy has a cytoreductive effect, and that LC could possibly augment an immunological response and survival benefit.

Substance use and substance use disorders show normative epidemiological age-related trends, with typically onset in the late adolescent to young adult years, manifesting peak prevalences in emerging adulthood, and decreasing thereafter. Although less prevalent in older adults, substance misuse is more consequential when present and thus represents a public health concern. Careful examination of the population-based empirical literature indicates the necessity of viewing substance involvement in the context of development, with unique developmental factors associated with its onset, course, and resolution. Many individuals who suffer from a substance use disorder appear to “recover” without formal treatment. Despite normative age-related trends, there is considerable individual course variation, and modern statistical techniques have identified several distinct prototypic courses that appear to differ in their determinants and consequences. Research using a lifespan perspective on substance use and misuse has powerful implications for the design of effective, developmentally informed prevention and intervention programs.

OBJECTIVES: Reports indicate that repair procedures for ischaemic mitral regurgitation (IMR) are less durable than previously thought. Repair failure has been shown to be stress related. Leaflet curvature is the major determinant of valve stress. Theoretical and animal experiments have shown that saddle-shaped annuloplasty optimizes leaflet curvature when compared with standard flat ring annuloplasty. Despite this, the influence of the ring shape on leaflet curvature has not been described in patients with IMR. This study uses real-time three-dimensional echocardiography (rt-3DE) to assess the influence of the ring shape on leaflet curvature. METHODS: Rt-3DE was performed in 21 patients with IMR after placement of either a flat (n= 10, CE-Physio, Edwards) or saddleshaped (n= 11, Profile 3D, Medtronic) annuloplasty ring. A combination of commercially available and customized software was used to measure multiple leaflet curvature parameters across all regions of the mitral valve. RESULTS: Independently of the shape of the annuloplasty ring, all patients were subject to the same degree of annular undersizing. Patients who received saddle-shaped annuloplasty rings had greater leaflet curvature in all six mitral valve leaflet regions (A1 = 0.36 ± 0.10, A2 = 0.53 ± 0.13, A3 = 0.47 ± 0.13, P1 = 0.35 ± 0.23, P2 = 0.53 ± 0.34, P3 = 0.42 ± 0.20 cm �2 ) compared with patients who received flat annuloplasty rings (A1 = 0.16 ± 0.11, A2 = 0.18 ± 0.09, A3 = 0.16 ± 0.11, P1 = 0.20 ± 0.17, P2 = 0.21 ± 0.11, P3 = 0.18 ± 0.13 cm �2 ). These differences were statistically significant in all regions except the P1 region. CONCLUSIONS: Saddle-shaped annuloplasty rings increase leaflet curvature compared with flat rings in patients with IMR. As a result, saddle-shaped annuloplasty may decrease leaflet stress and potentially increases the durability of the repair in patients with IMR.

Chromosome rearrangements are a significant cause of intellectual disability and birth defects. Subtelomeric rearrangements, including deletions, duplications and translocations of chromosome ends, were first discovered over 40 years ago and are now recognized as being responsible for several genetic syndromes. Unlike the deletions and duplications that cause some genomic disorders, subtelomeric rearrangements do not typically have recurrent breakpoints and involve many different chromosome ends. To capture the molecular mechanisms responsible for this heterogeneous class of chromosome abnormality, we coupled high-resolution array CGH with breakpoint junction sequencing of a diverse collection of subtelomeric rearrangements. We analyzed 102 breakpoints corresponding to 78 rearrangements involving 28 chromosome ends. Sequencing 21 breakpoint junctions revealed signatures of non-homologous end-joining, non-allelic homologous recombination between interspersed repeats and DNA replication processes. Thus, subtelomeric rearrangements arise from diverse mutational mechanisms. In addition, we find hotspots of subtelomeric breakage at the end of chromosomes 9q and 22q; these sites may correspond to genomic regions that are particularly susceptible to double-strand breaks. Finally, fine-mapping the smallest subtelomeric rearrangements has narrowed the critical regions for some chromosomal disorders.

High-throughput DNA sensors capable of detecting single-base mismatches are required for the routine screening of genetic mutations and disease. A new strategy for the electrochemical detection of single-base mismatches in DNA has been developed based upon charge transport through DNA films. Double-helical DNA films on gold surfaces have been prepared and used to detect DNA mismatches electrochemically. The signals obtained from redox-active intercalators bound to DNA-modified gold surfaces display a marked sensitivity to the presence of base mismatches within the immobilized duplexes. Differential mismatch detection was accomplished irrespective of DNA sequence composition and mismatch identity. Single-base changes in sequences hybridized at the electrode surface are also detected accurately. Coupling the redox reactions of intercalated species to electrocatalytic processes in solution considerably increases the sensitivity of this assay. Reporting on the electronic structure of DNA, as opposed to the hybridization energetics of single-stranded oligonucleotides, electrochemical sensors based on charge transport may offer fundamental advantages in both scope and sensitivity.