Van Den Heuvel Research Articles

Abstract 1184: Combination pembrolizumab and radiotherapy induces anti-tumor immune responses in immunologically-cold non-small cell lung cancer

Abstract Introduction: Primary resistance to immune checkpoint inhibition (ICI) is in part driven by a “cold” tumor microenvironment in the context of low PD-L1 expression, low tumor mutation burden or oncogenic mutations that drive tumor immune exclusion. Radiation has the potential to sensitize tumors to ICI through extra-tumoral T cell activation in response to tumor antigens released from irradiated cancer cells (abscopal effect). Here, we investigate tumor microenvironment and T cell repertoire reshaping leveraging serial biospecimens from a phase 2 randomized clinical trial of stereotactic body radiation therapy followed by pembrolizumab (SBRT arm) vs. pembrolizumab alone (control arm) in non-small cell lung cancer (NSCLC; NCT02492568). Methods: We employed whole exome sequencing, RNA sequencing and T cell receptor (TCR) sequencing to analyze 293 serial tumor and peripheral blood samples collected at baseline and after 8 weeks of treatment from 72 patients in the control (n=35) and SBRT (n=37) arms. Immunologically-cold tumors were defined as low TMB (<300 mutations per exome, n=43), PD-L1 null (0% expression on immunohistochemistry, n=41), or WNT-activated (presence of mutations affecting genes in the WNT pathway, n=10). TCR clonotypic differential abundance analyses and RNA sequencing deconvolution and gene set enrichment analyses were performed on baseline and on-therapy blood and tumor samples from the control and SBRT arms. Results: Patients with immunologically-cold tumors in the SBRT arm had significantly longer progression free survival compared to the pembrolizumab monotherapy arm (log rank p=0.029 for TMB-low, p=0.022 for PD-L1-null, p=0.037 for the WNT-activated subsets). Induction of interferon-gamma, interferon-alpha, antigen processing and presentation, and inflammatory response gene sets was significantly enriched on-therapy in the SBRT arm (FDR adjusted p<0.01 for TMB-low, PD-L1-null, and WNT-activated tumors). We observed greater enrichment in newly expanded TCR clones on-therapy intratumorally and in peripheral blood in the SBRT arm compared to the control arm (mean 16.17 vs 7.54 clonotypes, p=0.022 in tumor; mean 4.56 vs 1.00, p=0.039 in blood; Mann-Whitney U test). Similarly, we noted greater expansion of pre-existing TCR clones in the SBRT arm than within the control arm (mean 34.83 vs 18.69, p=0.021 in tumor; mean 21.61 vs 8.15, p=0.009 in blood; Mann-Whitney U test). Within the SBRT arm, there was no significant difference in T cell expansion between TMB-stratified (<300 mutations vs >=300 mutations) or PD-L1-stratified (0% vs >= 1% expression) groups. Conclusions: SBRT followed by pembrolizumab was associated with priming and augmenting anti-tumor immune responses in immunologically-cold NSCLC, which opens a therapeutic window of opportunity for radiotherapy to overcome primary resistance to immune checkpoint inhibition. Citation Format: Justin Huang, Willemijn S. Theelen, Zineb Belcaid, Mimi Najjar, Christopher Cherry, Archana Balan, James R. White, Noushin Niknafs, Jaime Wehr, M.M. van den Heuvel, Rachel Karchin, Paul Baas, Victor E. Velculescu, Valsamo Anagnostou. Combination pembrolizumab and radiotherapy induces anti-tumor immune responses in immunologically-cold non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1184.

An Ore-Type Condition for Hamiltonicity in Tough Graphs and the Extremal Examples

Let $G$ be a $t$-tough graph on $n\ge 3$ vertices for some $t>0$. It was shown by Bauer et al. in 1995 that if the minimum degree of $G$ is greater than $\frac{n}{t+1}-1$, then $G$ is hamiltonian. In terms of Ore-type hamiltonicity conditions, the problem was only studied when $t$ is between 1 and 2, and recently the second author proved a general result. The result states that if the degree sum of any two nonadjacent vertices of $G$ is greater than $\frac{2n}{t+1}+t-2$, then $G$ is hamiltonian. It was conjectured in the same paper that the "$+t$" in the bound $\frac{2n}{t+1}+t-2$ can be removed. Here we confirm the conjecture. The result generalizes the result by Bauer, Broersma, van den Heuvel, and Veldman. Furthermore, we characterize all $t$-tough graphs $G$ on $n\ge 3$ vertices for which $\sigma_2(G) = \frac{2n}{t+1}-2$ but $G$ is non-hamiltonian.

Functional connectome‐based prediction of individual clinical and cognitive scores in midlife population with risk of dementia

AbstractBackgroundIt is well acknowledged that Alzheimer’s Disease (AD) neuropathology start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. Resting‐state functional connectivity (FC) is increasingly used to understand early brain changes in Alzheimer’s disease (AD) (Sperling, 2011; van den Heuvel & Sporns, 2019). We asked whether risk for late‐life dementia impacts functional connectivity in cognitively healthy middle‐aged individuals.MethodFunctional Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 585 (207/378 female/male) cognitively healthy individuals, aged 40‐59 years (mean = 50.9), from the PREVENT‐Dementia study. Dementia risk was calculated with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score. A novel connectome‐based predictive method called NBS‐Predict was used to investigate the association between FC and CAIDE score and its role in cognition.ResultFC significantly predicted CAIDE scores across the whole cohort (r = 0.207, p < 0.001). FC within and between the cingulo‐opercular network (CON) and sensorimotor network (SMN), as well as between CON and fronto‐parietal network (FPN), and between SMN with default mode network (DMN), and FPN contributed the most (Figure 1). Furthermore, we found that, in the high dementia risk group (CAIDE > 6) only, FC, mainly in DMN‐SMN and DMN‐CON (Figure 2), significantly predicted multisensory processing cognitive score (r = 0.114, p<0.05).ConclusionOur results show that FC can be used to detect early brain changes associated with risk of future dementia in cognitively healthy individuals. This method has implications of the early detection of dementia in preclinical populations.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Social determinants of racial health inequities

Social determinants of racial health inequities

The Push to Integrate Mid-Level Providers into Dentistry

The Push to Integrate Mid-Level Providers into Dentistry

Automatic Registration Method of Multi-Source Point Clouds Based on Building Facades Matching in Urban Scenes

Both UAV photogrammetry and lidar have become common in deriv- ing three-dimensional models of urban scenes, and each has its own advantages and disadvantages. However, the fusion of these multi- source data is still challenging, in which registration is one of the most important stages. In this paper, we propose a method of coarse point cloud registration which consists of two steps. The first step is to extract urban building facades in both an oblique photogram- metric point cloud and a lidar point cloud. The second step is to align the two point clouds using the extracted building facades. Object Vicinity Distribution Feature (Dijkman and Van Den Heuvel 2002) is introduced to describe the distribution of building facades and register the two heterologous point clouds. This method provides a good initial state for later refined registration process and is transla - tion, rotation, and scale invariant. Experiment results show that the accuracy of this proposed automatic registration method is equiva- lent to the accuracy of manual registration with control points.

Vizing's and Shannon's Theorems for Defective Edge Colouring

We call a multigraph $(k,d)$-edge colourable if its edge set can be partitioned into $k$ subgraphs of maximum degree at most $d$ and denote as $\chi'_{d}(G)$ the minimum $k$ such that $G$ is $(k,d)$-edge colourable. We prove that for every odd integer $d$, every multigraph $G$ with maximum degree $\Delta$ is $(\lceil \frac{3\Delta - 1}{3d - 1} \rceil, d)$-edge colourable and this bound is attained for all values of $\Delta$ and $d$. An easy consequence of Vizing's Theorem is that, for every (simple) graph $G,$ $\chi'_{d}(G) \in \{ \lceil \frac{\Delta}{d} \rceil, \lceil \frac{\Delta+1}{d} \rceil \}$. We characterize the values of $d$ and $\Delta$ for which it is NP-complete to compute $\chi'_d(G)$. These results generalize classic results on the chromatic index of a graph by Shannon, Holyer, Leven and Galil and extend a result of Amini, Esperet and van den Heuvel.

Improved bound for improper colourings of graphs with no odd clique minor

AbstractStrengthening Hadwiger’s conjecture, Gerards and Seymour conjectured in 1995 that every graph with no odd $K_t$ -minor is properly $(t-1)$ -colourable. This is known as the Odd Hadwiger’s conjecture. We prove a relaxation of the above conjecture, namely we show that every graph with no odd $K_t$ -minor admits a vertex $(2t-2)$ -colouring such that all monochromatic components have size at most $\lceil \frac{1}{2}(t-2) \rceil$ . The bound on the number of colours is optimal up to a factor of $2$ , improves previous bounds for the same problem by Kawarabayashi (2008, Combin. Probab. Comput.17 815–821), Kang and Oum (2019, Combin. Probab. Comput.28 740–754), Liu and Wood (2021, arXiv preprint, arXiv:1905.09495), and strengthens a result by van den Heuvel and Wood (2018, J. Lond. Math. Soc.98 129–148), who showed that the above conclusion holds under the more restrictive assumption that the graph is $K_t$ -minor-free. In addition, the bound on the component-size in our result is much smaller than those of previous results, in which the dependency on $t$ was given by a function arising from the graph minor structure theorem of Robertson and Seymour. Our short proof combines the method by van den Heuvel and Wood for $K_t$ -minor-free graphs with some additional ideas, which make the extension to odd $K_t$ -minor-free graphs possible.

Abstract 666: A phase 1 study to detect adverse events after SBRT and immunotherapy by electronic nose in advanced NSCLC

Abstract It is increasingly understood that cancers can be recognized by the immune system and that inflammation relates to response. Combining stereotactic radiotherapy (SBRT) to increase release of cancer cell antigens with an anti-CTLA-4 and PD-L1 inhibitor may lead to increased response rates. Due to tumor heterogeneity it may be important to irradiate the primary tumor (addressing trunk mutations), instead of its metastasis (branch mutations). No solid predictive biomarker for response and/or immunotherapy related adverse events (TRAEs) is available. Electronic nose (eNose) technology measures the complete mixture of volatile organic compounds in exhaled breath and can detect lung cancer based on pattern recognition of the breath profile. We hypothesize that eNose is able to predict TRAEs and response in patients with NSCLC. Methods: In 3 sequential cohorts, immunotherapy regimes combined with SBRT were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. All patients were irradiated on the primary tumor (1x20 Gy on 9cc) 1 week after the 1st dose of immunotherapy. The 1st cohort (n=3) received durvalumab. The 2nd and 3rd cohort (both n=6) received a combination of durvalumab and tremelimumab followed by durvalumab monotherapy. Duplicate eNose measurements were performed by using the SpiroNose that contains 7 metal oxide semiconductor sensors. TRAEs were categorized using NCI CTCAE version 4.3. Descriptive statistics were used to summarize baseline characteristics and TRAEs. The relationship between breath profiles and response and TRAEs was analyzed with advanced signal processing, ambient correction and Mann-Whitney U test. Linear discriminant and receiver operating characteristics analysis followed. Pearson correlation and regression assessed duration of response. Findings: Fifteen patients were included as described above. Baseline characteristics of the groups were comparable. Median progression free survival was 2 months, overall survival 10 months (immature). No statistical difference was found in (duration of) response. There was 1 low grade TRAE (CTC 1-2) in cohort 1 and 10 in cohort 2/3. High grade TRAEs (CTC 3) were only present in cohort 2/3 (n=3) and 1 patient discontinued treatment. There was one dose limiting toxicity. At baseline, 12/15 patients performed eNose measurements; 7 with TRAEs and 5 without. The TRAE group had a significant higher sensor 7 signal compared to those without TRAE (p=.042). The cross-validated accuracy for detecting TRAE was 67%. The ROC-AUC was .857 [.638-1]. Interpretation: eNose breath profiles at baseline may predict which patients will develop TRAEs. The small sample size increases the risk of overfitting, therefore another cohort of 34 immuno-monotherapy patients is being analyzed (15 with and 19 without TRAEs, pending). We demonstrated no new safety data. Disclosure: This study was sponsored by a research grant from AstraZeneca. Citation Format: M Benthe Muntinghe-Wagenaar, Hanneke Kievit, Lucie B. Hijmering-Kappelle, Birgitta I. Hiddinga, J Fred Ubbels, Robin Wijsman, Mechteld F. Brasz, Gitte Slingers, Rianne de Vries, Milou M. Schuurbiers, Harry J. Groen, Huib A. Kerstjens, Anthonie J. van der Wekken, Michel M. van den Heuvel, T Jeroen Hiltermann. A phase 1 study to detect adverse events after SBRT and immunotherapy by electronic nose in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 666.

Theoretical analysis of the long-distance limit of NMR chemical shieldings.

After some years of controversy, it was recently demonstrated how to obtain the correct long-distance limit [point-dipole approximation (PDA)] of pseudo-contact nuclear magnetic resonance chemical shifts from rigorous first-principles quantum mechanics [Lang et al., J. Phys. Chem. Lett. 11, 8735 (2020)]. This result confirmed the classical Kurland-McGarvey theory. In the present contribution, we elaborate on these results. In particular, we provide a detailed derivation of the PDA both from the Van den Heuvel-Soncini equation for the chemical shielding tensor and from a spin Hamiltonian approximation. Furthermore, we discuss in detail the PDA within the approximate density functional theory and Hartree-Fock theories. In our previous work, we assumed a relatively crude effective nuclear charge approximation for the spin-orbit coupling operator. Here, we overcome this assumption by demonstrating that the derivation is also possible within the fully relativistic Dirac equation and even without the assumption of a specific form for the Hamiltonian. Crucial ingredients for the general derivation are a Hamiltonian that respects gauge invariance, the multipolar gauge, and functional derivatives of the Hamiltonian, where it is possible to identify the first functional derivative with the electron number current density operator. The present work forms an important foundation for future extensions of the Kurland-McGarvey theory beyond the PDA, including induced magnetic quadrupole and higher moments to describe the magnetic hyperfine field.

Revising the atherosclerotic cardiovascular disease calculator without race

Revising the atherosclerotic cardiovascular disease calculator without race

Cornelis de Jager

Cornelis de Jager (1921–2021) Astronomer, pioneer of European space research, inspiring teacher, and a popularizer of science, here remembered by Edward P J van den Heuvel. Kees de Jager was born on 29 April 1921 in Den Burg on the Dutch island of Texel, the place where he returned to live for his last 18 years. He spent his childhood in the Dutch East Indies (now Indonesia), where his father was principal of a primary school, first in North Celebes (now Sulawesi), where Kees attended primary school, and later on Java, where Kees completed his secondary education (HBS) in the city of Surabaya, where he also met Doetie Rienks, later his wife. The beautiful starry sky of Celebes made a deep impression on him. His father had already pointed out the different colours of the stars and told him that this meant that they had different temperatures, which sparked Kees's interest in astronomy.

SIX INCIDENTALLY DISCOVERED IDIOPATHIC PULMONARY ARTERIOVENOUS MALFORMATIONS

TOPIC: Procedures TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary arteriovenous malformations (PAVMs) are rare vascular abnormalities in which arterioles connect directly to venules without passing through a capillary bed. Up to 95% of all PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT). HHT is an autosomal dominant disease characterized by AVMs most notably affecting the pulmonary, hepatic, and cerebral circulations. Idiopathic PAVMs have a greater propensity to present as solitary malformations. We present the case of a patient with six incidentally discovered PAVMs. Further evaluation, including genetic testing not consistent with HHT, made this an unusual case of multiple presumed idiopathic PAVMs. CASE PRESENTATION: A 34-year-old female with a history of recent left ankle fracture was referred to the pulmonary clinic after an emergency department evaluation revealed six PAVMs on CT pulmonary angiogram following the diagnosis of a left lower extremity deep vein thrombosis. The largest PAVM (2.4 cm) was located in the right upper lobe and was classified as complex, having multiple segmental feeding arteries with a dominant draining vein. The remaining five were classified as simple AVMs, having a single feeding artery and draining vein. She endorsed a history of epistaxis, family history of stroke, and persistent borderline hypoxemia. An anatomic shunt study was performed with arterial blood gas measurements on room air and while breathing 100% oxygen with a calculated shunt fraction of 28%. Transthoracic echocardiogram showed normal pulmonary and central venous pressures. MRI brain revealed multiple punctate foci of enhancement most consistent with small vascular malformations. She underwent genetic testing for HHT (including ACVRL1, ENG, EPHB4, GDF2, RASA1, and SMAD4 genes) which was negative. The patient was referred to Interventional Radiology for coil embolization of the two largest PAVMs given her clinically significant right-to-left shunt. DISCUSSION: PAVMs cause impairment in gas exchange, filtration, and processing of systemic venous blood with a spectrum of clinical manifestations including life-threatening hemorrhage and paradoxical embolism. Although PAVMs are commonly asymptomatic, their unique complications include hypoxemia, dyspnea, hemoptysis, pulmonary hypertension, brain abscess, seizure, and stroke. There is evidence to suggest that idiopathic PAVMs act similarly to HHT-related PAVMs with comparable symptoms and plausible clinical complications. CONCLUSIONS: Clinical presentation may vary widely, however, PAVMs are important to recognize and evaluate for need for intervention, even if asymptomatic, given their potential for serious sequelae if left untreated. REFERENCE #1: Shovlin, CL. Pulmonary Arteriovenous Malformations. Am J Respir Crit Care Med 2014; 190 (11): 1217-28. REFERENCE #2: Wong HH, Chan RP, Klatt R, Faughnan ME: Idiopathic pulmonary arteriovenous malformations: clinical and imaging characteristics. Eur Respir J 2011; 38: 368-75. REFERENCE #3: Kroon S, van den Heuvel DAF, Vos JA, et al. Idiopathic and hereditary haemorrhagic telangiectasia associated pulmonary arteriovenous malformations: comparison of clinical and radiographic characteristics. Clin Radiol. 2021;76(5):394. DISCLOSURES: No relevant relationships by Sarah Kemp, source=Web Response No relevant relationships by Patrick Kicker, source=Web Response

Occupational Health, Productivity and Evidence-Based Workplace Health Intervention

Occupational Health, Productivity and Evidence-Based Workplace Health Intervention

IRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation.

Post-translational modification of ribosomal proteins enables rapid and dynamic regulation of protein biogenesis. Site-specific ubiquitylation of 40S ribosomal proteins uS10 and eS10 plays a key role during ribosome-associated quality control (RQC). Distinct, and previously functionally ambiguous, ubiquitylation events on the 40S proteins uS3 and uS5 are induced by diverse proteostasis stressors that impact translation activity. Here, we identify the ubiquitin ligase RNF10 and the deubiquitylating enzyme USP10 as the key enzymes that regulate uS3 and uS5 ubiquitylation. Prolonged uS3 and uS5 ubiquitylation results in 40S, but not 60S, ribosomal protein degradation in a manner independent of canonical autophagy. We show that blocking progression of either scanning or elongating ribosomes past the start codon triggers site-specific ubiquitylation events on ribosomal proteins uS5 and uS3. This study identifies and characterizes a distinct arm in the RQC pathway, initiation RQC (iRQC), that acts on 40S ribosomes during translation initiation to modulate translation activity and capacity.

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa

No Evident Systemic Terminal Complement Pathway Activation in Hidradenitis Suppurativa

Flogging a Dead Salmon? Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials

Flogging a Dead Salmon? Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials

Distances to Galactic X-ray binaries with Gaia DR2

ABSTRACT Precise and accurate measurements of distances to Galactic X-ray binaries (XRBs) reduce uncertainties in the determination of XRB physical parameters. We have cross-matched the XRB catalogues of Liu, van Paradijs & van den Heuvel to the results of Gaia Data Release 2. We identify 86 XRBs with a Gaia candidate counterpart, of which 32 are low-mass X-ray binaries (LMXBs) and 54 are high-mass X-ray binaries (HMXBs). Distances to Gaia candidate counterparts are, on average, consistent with those measured by Hipparcos and radio parallaxes. When compared to distances measured by Gaia candidate counterparts, distances measured using Type I X-ray bursts are systematically larger, suggesting that these bursts reach only 50 per cent of the Eddington limit. However, these results are strongly dependent on the prior assumptions used for estimating distance from the Gaia parallax measurements. Comparing positions of Gaia candidate counterparts for XRBs in our sample to positions of spiral arms in the Milky Way, we find that HMXBs exhibit mild preference for being closer to spiral arms; LMXBs exhibit mild preference for being closer to interarm regions. LMXBs do not exhibit any preference for leading or trailing their closest spiral arm. HMXBs exhibit a mild preference for trailing their closest spiral arm. The lack of a strong correlation between HMXBs and spiral arms may be explained by star formation occurring closer to the mid-point of the arms, or a time delay between star formation and HMXB formation manifesting as a spatial separation between HMXBs and the spiral arm where they formed.

Stephen F. Cohen (1938–2020)

Stephen F. Cohen (1938–2020) Alexander Rabinowitch My decades-long friendship with the late Stephen F. (Steve) Cohen, eminent historian of 20th-century Russia and courageous public intellectual, began in the fall of 1961, when we were graduate students in Russian/Soviet studies at Indiana University, Bloomington (IU).1 Having recently received an MA in international relations and history at the University of Chicago, I was completing course requirements for the PhD in Russian history at IU. Steve, who originally came to IU on a partial golf scholarship, had received a BS in economics and public policy and was then completing requirements for an MA in government and Russian studies. Already at that time, the IU Russian and East European Institute (REEI) was one of the premier American centers for interdisciplinary study of Russia, with especially great strength in Soviet politics, culture, and history. The historically grounded approach to studying that part of the world practiced by my primary adviser, the noted diplomatic historian and innovative pedagogue John M. Thompson, and Steve's chief mentor, the distinguished political theorist and leading Sovietologist Robert C. Tucker, dovetailed. This was also the approach of a large cohort of advanced graduate students with Soviet and East European specializations in both the government and history departments at IU. We tended to take many of the same courses, frequently developed related scholarly interests, and formed close, sometimes lifelong, mutually supportive friendships—as was the case with Steve and me. In the spring of 1962, Tucker accepted a permanent senior position at Princeton University and left IU. At about the same time, Steve received an MA in government and Soviet studies and transferred to Columbia University to begin work on a PhD in Russian studies. However, my close association with him continued during the 1962–63 academic year, when I was [End Page 430] conducting research in New York libraries and archives for my doctoral dissertation on the Bolsheviks and the July 1917 uprising in Petrograd. During that period, we met often, as both of us were living just four blocks apart on New York's Upper West Side, not far from the Columbia campus. One of the last times I saw Steve was in September 2019, when we, together with our spouses and soul mates (Katrina vanden Heuvel, the editorial director and publisher of The Nation with extensive firsthand experience in Moscow; and Janet Rabinowitch, a historian of modern Russia and long-time senior editor and director of Indiana University Press), participated in an REEI-sponsored roundtable titled "Russian Odysseys." The "odysseys" were Steve's and mine. We were to reflect on the roots of our long engagement with Russia, the importance of our educational experience at IU, and our professional careers in the Russian studies field. In addition to both of us being IU alums, the university had been my home base for most of my professional life, while Steve and Katrina had been generous supporters of REEI's student financial aid program and were frequent, always well-received guest lecturers. According to the roundtable format developed by Katrina and Janet, they were to take turns "deposing" us. The large, informal room where the event took place was packed for the occasion—Steve and Katrina could always be counted on to draw big crowds. The mood was friendly and relaxed, yet focused. This was due largely to Steve, whose pioneering research on the Soviet historical experience was well known and greatly admired, and who was as engaging, intellectually lively, and even entertaining in such congenial surroundings as he was crisp, quick, passionate, and often simply overwhelming in serious semiprivate or public debate. To give a few examples from our "odyssey" roundtable: I responded to an initial question from Janet about how and when my Russian odyssey began by describing my birth and upbringing in a prominent Russian émigré family. Responding to a follow-up question from Katrina about what had brought me to IU and the impact of my IU experience, I described the effect of my youthful interactions with prominent Russian refugees, military service, and the first Cold War on the formation of my early, thoroughly negative view of Soviet history and politics...