Showing papers by "David Spiegel published in 2018"

Racial and Ethnic Disparities in Cancer Survival: The Contribution of Tumor, Sociodemographic, Institutional, and Neighborhood Characteristics

Abstract: Purpose Racial/ethnic disparities in cancer survival in the United States are well documented, but the underlying causes are not well understood. We quantified the contribution of tumor, treatment, hospital, sociodemographic, and neighborhood factors to racial/ethnic survival disparities in California. Materials and Methods California Cancer Registry data were used to estimate population-based cancer-specific survival for patients diagnosed with breast, prostate, colorectal, or lung cancer between 2000 and 2013 for each racial/ethnic group (non-Hispanic black, Hispanic, Asian American and Pacific Islander, and separately each for Chinese, Japanese, and Filipino) compared with non-Hispanic whites. The percentage contribution of factors to overall racial/ethnic survival disparities was estimated from a sequence of multivariable Cox proportional hazards models. Results In baseline models, black patients had the lowest survival for all cancer sites, and Asian American and Pacific Islander patients had the highest, compared with whites. Mediation analyses suggested that stage at diagnosis had the greatest influence on overall racial/ethnic survival disparities accounting for 24% of disparities in breast cancer, 24% in prostate cancer, and 16% to 30% in colorectal cancer. Neighborhood socioeconomic status was an important factor in all cancers, but only for black and Hispanic patients. The influence of marital status on racial/ethnic disparities was stronger in men than in women. Adjustment for all covariables explained approximately half of the overall survival disparities in breast, prostate, and colorectal cancer, but it explained only 15% to 40% of disparities in lung cancer. Conclusion Overall reductions in racial/ethnic survival disparities were driven largely by reductions for black compared with white patients. Stage at diagnosis had the largest effect on racial/ethnic survival disparities, but earlier detection would not entirely eliminate them. The influences of neighborhood socioeconomic status and marital status suggest that social determinants, support mechanisms, and access to health care are important contributing factors.

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks

Abstract: Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO) Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1 Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism

A Review of the Neurobiological Basis of Trauma-Related Dissociation and Its Relation to Cannabinoid- and Opioid-Mediated Stress Response: a Transdiagnostic, Translational Approach

Abstract: Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb's threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model.

The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review.

Abstract: This article reviews the role of the vagus nerve in tumor modulation and cancer prognosis. We present a systematic review of 12 epidemiological studies examining the relationship between heart rate variability, the main vagus nerve index, and prognosis in cancer patients (survival and tumor markers). These studies show that initially high vagal nerve activity predicts better cancer prognosis, and, in some studies, independent of confounders such as cancer stage and treatments. Since the design of the epidemiological studies is correlational, any causal relationship between heart rate variability and cancer prognosis cannot be inferred. However, various semi-experimental cohort studies in humans and experimental studies in animals have examined this causal relationship. The second part of this paper presents a comprehensive review including human and animal cohort and experimental studies showing that vagotomy accelerates tumor growth, while vagal nerve activation improves cancer prognosis. Based on all reviewed studies, it is concluded that the evidence supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage.

Serum-to-dialysate potassium gradient and its association with short-term outcomes in hemodialysis patients.

Abstract: Background A high serum-to-dialysate potassium (K+) gradient at the start of dialysis leads to rapid lowering of serum K+ and may confer a greater risk of adverse events. Here, we examined the near-term association of K+ gradient with clinical outcomes. Methods This retrospective (2010-11) event-based study considered 830 741 patient-intervals, each defined by a pre-dialysis measurement of serum K+ made among adult Medicare Parts A and B enrollees who received in-center hemodialysis on a Monday/Wednesday/Friday schedule at a large US dialysis organization. K+ gradient was considered based on the difference in K+ concentration (serum-dialysate) on the date of measurement; analyses accounted for multiple observations per patient. Outcomes considered were: all-cause and cardiovascular hospital admissions, emergency department (ED) visits and deaths. Results Higher K+ gradient was associated with younger age, greater fistula use, lower comorbidity scores and better nutritional indices. Adjusting for patient differences, there was a dose-response relationship between higher K+ gradient and greater risks of all-cause hospitalization and ED visit. A similar trend was seen for cardiovascular hospitalization but did not achieve statistical significance. No associations were observed with mortality, potentially due to a low number of events. Conclusions Higher K+ gradient is independently associated with greater risk of all-cause hospitalizations and ED visits. Further research is needed to determine whether interventions that reduce the K+ gradient ameliorate this risk.

Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer

Abstract: Background Psychosocial symptoms often cluster together, are refractory to treatment, and impair health‐related quality of life (HR‐QoL) in cancer patients. The contribution of circadian rhythm alterations to systemic symptoms has been overlooked in cancer, despite a causal link shown under jet lag and shift work conditions. We investigated whether the circadian rest‐activity rhythm provides a reliable and objective estimate of the most frequent patient‐reported outcome measures (PROMs). Methods Two datasets were used, each involving concomitant 3‐day time series of wrist actigraphy and HR‐QoL questionnaires: EORTC QLQ‐C30 was completed once by 237 patients with metastatic colorectal cancer; MD Anderson Symptom Inventory (MDASI) was completed daily by 31 patients with advanced cancer on continuous actigraphy monitoring, providing 1015 paired data points. Circadian function was assessed using the clinically validated dichotomy index I < O. Nonparametric tests compared PROMs and I < O. Effect sizes were computed. Sensitivity subgroup and temporal dynamics analyses were also performed. Results I < O values were significantly lower with increasing symptom severity and worsening HR‐QoL domains. Fatigue and anorexia were worse in patients with circadian disruption. The differences were both statistically and clinically significant (P < 0.001; d ≥ 0.33). Physical and social functioning, and global quality/enjoyment of life were significantly better in patients with robust circadian rhythm (P < 0.001; d ≥ 0.26). Sensitivity analyses validated these findings. Conclusion Objectively determined circadian disruption was consistently and robustly associated with clinically meaningfully severe fatigue, anorexia, and interference with physical and social functioning. This supports an important role of the circadian system in the determination of cancer patients’ HR‐QoL and symptoms that deserves therapeutic exploitation.

Trauma-Related Dissociation Is No Fantasy: Addressing the Errors of Omission and Commission in Merckelbach and Patihis (2018)

Abstract: Dissociation is commonly a response to trauma that can be associated with significant impairment. In order to deal with dissociation in court from a comprehensive, scientifically informed, and valid perspective, Brand, Schielke, and Brams (Psychological Injury and Law, 10, 283-297, 2017a, b) provided a balanced view of dissociation, its characteristics, evidence base, and best assessment practices. Without an approach such as this, forensic experts risk having insufficient knowledge in its causation, phenomenology, and assessment and accordingly misunderstand trauma-related dissociation (TRD). Brand et al. (Psychological Injury and Law, 10, 283-297, 2017a, b) addressed this issue by providing an overview of TRD relevant to forensic contexts, acknowledging some of the erroneous and misinformed approaches to the topic. Merckelbach and Patihis (2018) offered a critique of Brand et al. (Psychological Injury and Law, 10, 283-297, 2017a, b) that illustrated this lack of knowledge and misunderstanding about TRD. Many of the statements made by these authors are conceptually inaccurate or scientifically misinformed. As we show, they were incorrect when they stated that research is lacking about the inter-rater reliability of dissociative disorder (DD) diagnoses. They were unaware of the error rates of tests and interviews among dissociative samples, which we present here. Merckelbach and Patihis challenged Brand et al., arguing their methods and literature review “lacked a connectivity to existing science” (p. 3), despite extensive citations of studies with DD patients. They argued that we failed to adequately consider malingering despite our discussions of empirically supported methods for assessing it. We show that Merckelbach and Patihis overlooked research that does not support their views. As we review their comments, we illustrate their pattern of misreading and misunderstanding our papers, as well as lapses in their reasoning. The current paper reinforces that in the forensic context, experts can acquire adequate understanding of TRD and its evidence base, and put forward arguments against any harsh critique of the area that is uninformed about, misunderstands, or includes omissions and errors in critical conceptualization, state-of-the-art assessment practices, and research methodology and results.

Distress and quality of life in an ethnically diverse sample awaiting breast cancer surgery.

Abstract: Poor breast cancer-related quality of life is associated with flattened cortisol rhythms and inflammation in breast cancer survivors and women with advanced disease. We explored the associations of cancer-specific distress (Impact of Events Scale), mood (Profile of Mood States), activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient) and cortisol (diurnal slope) circadian rhythms, and inflammation (interleukin-6) with quality of life (Functional Assessment of Cancer Therapy-Breast) among patients awaiting breast cancer surgery ( N = 57). Models were adjusted for differences in age and cancer stage. Distress and mood disturbance were significantly correlated with lower quality of life. Ethnic differences in the relationship between distress and mood disturbance with global quality of life and subscales of quality of life were observed. Actigraphic measures showed that in comparison with non-Hispanic patients, African Americans had significantly poorer activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient). Circadian disruption and inflammation were not associated with quality of life. Physiological dysregulation and associated comorbidities may take time to develop over the course of disease and treatment.

Virtual environments in cancer care: Pilot-testing a three-dimensional web-based platform as a tool for support in young cancer patients

Abstract: Bringing virtual environments into cancer support may offer a particular potential to engage patients and increase adherence to treatment. Developing and pilot-testing an online real-time multi-user three-dimensional platform, this study tested the use of an early prototype of the platform among adolescent and young adult cancer patients. Data were collected with an online questionnaire and using ethnographic methods of participant observation. The adolescent and young adult patients tested basic features of the virtual environment and some conducted brief in-world interactions with fellow patients during hospitalization. They had no reservations about using the technology and shared their ideas about its use. Our pilot test pointed to a number of areas of development for virtual environment applications as potential platforms for medical or behavioral interventions in cancer care. Overall, the results demonstrate the need for high user involvement in the development of such interventions and early testing of intervention designs.

Intra-operative computed tomography guided navigation for pediatric pelvic instrumentation: A technique guide.

Abstract: Pelvic instrumentation for neuromuscular scoliosis has been part of neuromuscular scoliosis surgery since the era of the Luque Galveston construct. Unit Rod (Medtronic Sofamor-Danek, Nashville, TN) instrumentation brought with it the concept of cantilever correction by placing the implants in the pelvis and then gradually bringing the rod to the spine by sequentially tightening the sublaminar wires, with the goal of creating a level pelvis over a straight spine. More recently surgeons have utilized pedicle screw constructs in which the corrective strategies have varied. Challenges with pelvic fixation using iliac screws linked to the spinal rod have led to the development of the S2-alar-iliac technique (S2AI) in which the spinal rod connects to the pelvic screw. The screw is placed in the S2 ala, crosses the sacro-iliac joint and into the ilium through a large column of supra-acetabular bone. This column is the same area used for anterior inferior iliac spine external fixation frames used in trauma surgery. S2AI screw placement can be technically difficult and can require experienced radiology technologists to provide the appropriate views. Additionally, although the technique was originally described being placed via freehand technique with intra-operative flouroscopy, the freehand technique suffers from the anatomic anomalies present in the pelvis in neuromuscular scoliosis. As such, we prefer to place them using intra-operative navigation for all pediatric spinal deformity cases. Below in detail we report our intra-operative technique and an illustrative case example.

Serotonin transporter polymorphism, depressive symptoms, and emotional impulsivity among advanced breast cancer patients

Abstract: This study tested a theory linking a marker of low serotonergic function to both depression and impulsivity in a sample of advanced breast cancer patients, among whom elevated depressive symptoms and difficulty regulating emotions are commonly reported. A total of 95 patients provided blood samples for serotonin transporter polymorphic region of the gene (5-HTTLPR) and completed questionnaires that measured depressive symptoms and emotional impulsivity. Structural equation modeling revealed that the s allele of 5-HTTLPR was related to greater depressive symptoms (β = .20, p < .042) but only marginally to greater emotional impulsivity (β = .19, p < .068). Depressive symptoms and emotional impulsivity were positively related (β = .33, p < .003). Further tests explored possible mediation from genotype to one psychological variable via the other. Results suggest that depressive symptoms, particularly perceived interpersonal rejection, may be a pathway linking genotype to emotional impulsivity. Findings provide the first evidence that low serotonergic function contributes to both depression and impulsivity within a clinically meaningful sample. Furthermore, the link of s allele of 5-HTTLPR to emotional impulsivity was mediated by depressive symptoms, particularly perceptions of social rejection. Findings have implications for advanced breast cancer patients’ treatment decision.

Circadian rhythms, sleep, and anti-cancer treatments

Abstract: The circadian timing system temporally regulates biological functions relevant for psycho-physical wellbeing, spanning all the systems related to health. Hence, disruption of circadian rhythms, along with sleep cycles, is associated with the development of several diseases, including cancer. Moreover, altered circadian and sleep functions negatively impact on cancer patients’ quality of life and survival, above and beyond known determinants of outcome. This alteration can occur as a consequence of cancer, but also of anti-cancer treatments. Indeed, circadian rhythms govern also the ability of detoxifying chemotherapy agents across the 24 hours. Hence, adapting chemotherapy delivery to the molecular oscillations in relevant drug pathways can decrease toxicity to healthy cells, while increasing the number of cancer cells killing. This chronomodulated chemotherapy approach, together with the maintenance of proper circadian function throughtout the whole disease challenge, would finally result in safer and more active anticancer treatments, and in patients experiencing better quality and quantity of life.

Compositions and Methods for Inducing an Immune Response

Abstract: The invention provides a modified cell having an immunomodulatory molecule bound to the cell surface. In some aspects, the invention provides compositions and methods for the treatment and prevention of a microbial infection and microbial infection-related diseases and disorders. The present invention also provides methods of inducing an immune response against a pathogen.

Infection Control in Pediatric Spinal Deformity Surgery: A Critical Analysis of Cause and Prevention Strategies in Adolescent Idiopathic Scoliosis, Neuromuscular Scoliosis, and Early Onset Scoliosis

Abstract: Purpose Surgical site infections (SSIs) significantly impact post-surgical morbidity and cost of care in pediatric spinal deformity surgery. While there have been prior attempts to identify preventative strategies and risks factors, few practice guidelines exist. Methods We performed a systematic review in April 2016, searching Pubmed, EMBASE, and Cochrane databases. Search terms were scoliosis, scolio*, spine, spin*, infection, and infect*. The search returned 4,436 studies from 2012 (when a prior review was performed) to the present. After application of …

Identification of Glucosepane Cross-Link Breaking Enzymes

Abstract: Glucosepane is a member of the class of advanced glycation end-products (AGEs), which form non-enzymatically in the human body. Glucosepane, is the most abundant AGE found in human collagen and has been implicated in the pathophysiology of various conditions ranging from diabetes to normal human aging. Glucosepane crosslinks impact the structural and mechanical properties of collagen and contribute to stiffening of collagenous tissues and vascular dysfunction. We have previously demonstrated the total synthesis of glucosepane, enabling methods for detecting and targeting glucosepane. The present study seeks to identify enzymes that are capable of catalyzing the decomposition of synthetic glucosepane crosslinks. To identify glucosepane crosslink breaking enzymes, we developed a novel screening technology based on metagenomics. Using this strategy, four enzymes were identified for in vitro validation of glucosepane degradation activity. Thus far, our efforts have focused on identifying metabolites of one class I-like enzyme in particular, since it is heterologously expressed at high levels and does not require any unusual cofactors. In vitro enzymatic assays showed that incubation of glucosepane with the class I-like enzyme led to a product consistent with citrulline. We are currently in the process of evaluating the enzyme’s mechanisms of action and identifying other metabolites generated. This is the first demonstration that glucosepane can be broken down enzymatically. Our findings may provide new insight into the role of glucosepane in aging and disease and aid in the development of novel therapeutic strategies for targeting glucosepane. Disclosure M. Streeter: None. T.N. Goddard: None. J.M. Crawford: None. D.A. Spiegel: None.

A Slick Solution to a Sticky Problem.

Abstract: Samir Gautam,†,‡ Lokesh Sharma,† Charles S. Dela Cruz,† and David Adam Spiegel*,‡ †Internal Medicine, Section of Pulmonary and Critical Care, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, United States ‡Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06520, United States A Viewpoint for Biochemistry on the article in Cell, “Immunomimetic Designer Cells Protect Mice from MRSA Infection” In his 2002 essay entitled “Can a biologist fix a radio?Or, what I learned while studying apoptosis”, Yuri Lazebnik chides the biology community for its over-reliance on reductionistic experimental techniques such as genetic deletion to describe complex systems. He humorously illustrates his argument by describing how a biologist might attempt to fix a radio, including the obligatory annihilation of each electrical component “at close range with metal particles” to determine its function, an approach analogous to the murine knockout experiments upon which biologists so depend. In contrast, he submits that an engineer would solve the problem handily based on a facility with standardized technical language (electrical diagramming) that fully and unambiguously describes the mechanical device. The rub, of course, is that radios are built by engineers in the first place; cells, much less animals, are not. Indeed, a principle advantage engineers hold over biologists in terms of “handiness” derives from a hundred years of research into the fundamental principles of electromagnetism and another hundred in refining the practice of electrical engineering, which allows them to create electrical devices according to a standardized methodology. A similar position of privilege is enjoyed by modern organic chemists, who have likewise spent centuries designing and synthesizing a huge array of small molecules and natural products, including the chemical therapeutics that serve as the backbone of modern medicine, to establish a robust fundamental and technical appreciation for how molecules behave. Accordingly, it might be stated that the true understanding of a system, as achieved in areas of physics and chemistry, is indicated by the ability to construct one. In recent years, biologists have made strides toward this lofty goal as they have endeavored to create cells, either from scratch in the case of synthetic biology or by modifying existing cells for therapeutic ends. A particularly successful example of the latter comes from immuno-oncologists, who have genetically engineered T-cells to express specific sensors for cancer antigens called chimeric antigen receptors (CARs). Ligation of these receptors elicits robust effector responses (cytokine release by CD4+ cells and direct cytotoxicity by CD8+ cells), leading to the elimination of targeted tumor cells (Figure 1). The clinical success of CAR T-cells in the treatment of advanced hematologic malignancies is unprecedented; for instance, anti-CD19 CAR-T therapy induces complete remission in ∼90% of patients with chemo-resistant B cell leukemias, in whom life expectancy would otherwise be months. Now, Liu et al. apply this engineering principle to develop a novel therapeutic for infectious disease. They target methicillin-resistant Staphylococcus aureus (MRSA), a Grampositive bacterium that is responsible for more deaths in the United States than any other bacterial pathogen, and can infect virtually any tissue, including blood, lung, and skin. A particularly feared form of MRSA infection is establishment of biofilms on implanted hardware, such as prosthetic joints or heart valves, which almost invariably necessitates surgical removal of the foreign material due to resistance of the associated biofilms to antibiotics. To tackle this problem, Liu et al. construct an elegant genetic network consisting of three principal components (Figure 1): (i) a sensing mechanism for constituents of the S. aureus cell wall, namely, lipoproteins and wall teichoic acids, which are detected via the cell-surface pathogen recognition receptors TLR1, TLR2, and TLR6, along with the co-receptor CD14; (ii) a highly optimized signal transduction module based on the immune transcription factors NFκB and AP-1 and the promoter for interferon-β; and (iii) a response element leading to expression of proteins that function as either diagnostics (secreted alkaline phosphatase) or therapeutics