bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA04: Impact of tumor-resident DC on antitumor immunity
Authors: Spranger Stefani
Published: March 2020

Clearance of tumors relies heavily on the production and maintenance of poly-functional CD8+ T-cell responses. Studies of antiviral and antitumor responses highlight that loss of T-cell effector functions, a phenomenon termed T-cell dysfunction or exhaustion, is associated with tumor evasion and is characteristic of a failed immune response. While this correlation is widely appreciated and the T cell-intrinsic mechanisms are well understood, our current understanding of the T cell-extrinsic stimuli that determine T-cell dysfunction versus sustained effector function remains rudimentary. Studies highlight that T-cell dysfunction is induced in tissue microenvironments characterized by high antigen density such as the tumor or the tumor-draining lymph node. Recent studies using mouse models and patient samples suggest that tumor-resident dendritic cells (DC) can have extensive impact on effector T-cell recruitment and function. Based on these observations, it is conceivable that local, nonmigratory DC subsets can engage directly with antigen-specific T cells and impact their effector function by supplying stimulatory or inhibitory signals. We have established model systems of cancer recapitulating the optimal, immunotherapy-sensitive, and immunotherapy-resistant phenotypes. Our data suggest that optimal antitumor immune responses are associated with the presence of a novel subset of DC, which we termed interferon-stimulated gene (ISG)-DC. Our data highlight that ISG-DC are a distinct subset of DC, capable of activating CD8+ T cells and providing a distinct set of costimulatory molecules to re-engage T cells. Mechanistic studies highlight that ISG-DC use an unconventional way of antigen presentation and are sensitized by tumor-derived dsRNA. In sum, we have identified a novel DC subset, which should be further explored for therapeutic engagement.

Citation Format: Stefani Spranger. Impact of tumor-resident DC on antitumor immunity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA04.
Abstract IA06: Optimizing T-cell receptor gene therapy for cancer
Authors: Chapuis Aude G.
Published: March 2020

My lab is translating T-cell receptor (TCR)-engineered T-cell therapies for patients with solid and liquid tumors, working to understand relevant immune escape mechanisms and developing strategies to circumvent obstacles to clinical efficacy. To advance optimally safe and effective TCRs, we devised a system to identify the highest-affinity TCRs from the pooled peripheral repertoires of human leukocyte antigen (HLA)-matched donors, from which autoreactive clones had been removed by thymic selection. In the solid-tumor realm, we developed adoptive T-cell therapy for patients with Merkel cell carcinoma (MCC), a virus-driven cancer that is an ideal model to test TCR-based treatments targeting non-self epitopes. We treated patients using autologous Merkel cell polyomavirus (MCPy)-specific CD8+ T-cell lines and an immune checkpoint inhibitor. Dramatic tumor reductions were associated with dense infiltrates of activated T cells in two patients, but relapses occurred 22 and 18 months later. Single-cell RNA sequencing (scRNAseq) identified dynamic transcriptional suppression of the targeted HLAs, suggesting strong and specific immunologic pressure of therapeutic T cells. To address HLA downregulation as a tumor escape mechanism, we have initiated a trial utilizing a high-affinity HLA A*0201-restricted TCR to engineered autologous T cells, thus conferring a high-affinity TCR to all patients. As soon as safety is confirmed with this TCR alone, T cells carrying other MCPy-targeting TCR(s) with alternate HLA restrictions will be combined. Overall, revealing the in vivo escape mechanisms that undermine the efficacy of transgenic T-cell therapy in patients can inform significant improvements in the design of TCR-engineered immunotherapies.

Citation Format: Aude G. Chapuis. Optimizing T-cell receptor gene therapy for cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA06.
Abstract IA08: Understanding resistance to develop next-generation CART for lymphoid malignancies
Authors: Ruella Marco
Published: March 2020

Adoptive T-cell therapies, and in particular chimeric antigen receptor T cells (CART), are leading to significant responses in cancer patients, particularly in B-cell leukemias and lymphomas. However, a significant subset of patients still do not respond or eventually relapse after anti-CD19 CART therapy. In his talk, Dr. Ruella will highlight recent finding in the pathogenesis of relapse after CART19 and discuss novel therapeutic approaches aimed at increasing CART feasibility and efficacy.

Citation Format: Marco Ruella. Understanding resistance to develop next-generation CART for lymphoid malignancies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA08.
Abstract IA12: Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy
Authors: Baylin Stephen B.
Published: March 2020

Despite the tremendous contribution made to date by immune checkpoint therapy to cancer management, most patients with the most common and deadliest forms of advanced cancer still do not receive durable benefit. Achieving manifest responses initially, understanding what predicts and contributes to long-term overall survival, and how to reverse initial or evolved resistance are all still major challenges to be addressed. Developing combinatorial approaches that may contribute to all of the above issues is a major goal, and epigenetic therapy is in play as one strategy for this purpose. Key specific points of the overall potential for the merits of combining this latter approach with immune checkpoint and other immunotherapies will be discussed in this presentation and include: 1) Critical steps in tumor immune evasion are under epigenetic control and can be reversed experimentally. There is evidence emerging that this also may be accomplished in patients and with epigenetic therapy drugs clinically available and in clinical trials such as DNA methyltransferase (DNMTis) and histone deactylase inhibitors (HDACis). The above steps for these drugs include restoration of tumor antigen presentation processes, restoration of tumor cell signaling for attraction of key antitumor subsets of immune cells, repulsion from tumors of key cells that promote immune tolerance, and repression of key oncogenic signaling pathways that otherwise suppress these above tumor immune attraction signals. 2) Key facets of immune tolerance inherent to signaling in immune cell subsets are under the control of epigenetic processes, and these too can be reversed by the types of drugs listed above, including T-cell and other immune cell exhaustion signaling, behavior of key ligands and receptors on immune cells critical for their migration to tumor cell sites and attack of cancer cells. Key experimental data for the above processes, coming from our own lab group and many collaborations within our participation in the Van Andel Institute – Stand Up To Cancer (VAI-SU2C) epigenetic therapy dream team, will be presented to support the hypotheses articulated above. Barriers to achieving efficacy of the approach, including which drugs will ultimately prevail, how to best sequence administration of the drugs, what cancer stages are most optimal for therapy institution, and what molecular parameters are promising for predicting efficacy, will also be discussed.

Citation Format: Stephen B. Baylin. Epigenetic therapy—potential efficacy for enhancing immune checkpoint therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA12.
Abstract IA13: Reprogramming the epigenome for enhancing CAR T-cell antitumor efficacy
Authors: Fraietta Joseph A.
Published: March 2020

Many studies indicate that adoptive cell transfer therapy with autologous chimeric antigen receptor (CAR) T cells is a powerful approach for the treatment of cancer. CAR-modified T cells have shown activity in several clinical trials including our own at the University of Pennsylvania, with complete response rates as high as 80-90% in certain malignancies. However, the effectiveness of this approach for cancers involving T-cell defects, such as multiple myeloma, pancreatic cancer, and chronic lymphocytic leukemia (CLL), is much lower. The key questions currently facing the field are how to: i) enhance the potency and sustain the in vivo function of CAR T cells for such indications and ii) develop strategies to increase the resistance of CAR T cells to intrinsic and extrinsic dysfunction (e.g., immunosenescence, exhaustion, or other disease-specific defects). Because cell fate determination programs encoded in DNA are interpreted, modified, transmitted, and expanded as chromatin, we hypothesize that immunotherapy and reversal of T-cell dysfunction in cancer can be improved by broadly or specifically targeting appropriate epigenetic pathways. In this vein, we explore manipulation of the “writers” and “readers” of the histone code using genetic editing tools (e.g., CRISPR/Cas9) and chemical modifiers to convert poorly functional T cells to a state that renders these lymphocytes effective at tumor elimination. The basic understanding of T-cell biology in the context of epigenetic regulation may result in enhancement of cellular immunotherapy strategies, including the discovery of several actionable improvements to CAR T-cell therapy.

Citation Format: Joseph A. Fraietta. Reprogramming the epigenome for enhancing CAR T-cell antitumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA13.
Abstract IA16: Whole-body PD-L1 and PD-1 PET: First-in-human experience
Authors: Leung David
Published: March 2020

Interaction between PD-L1 and PD-1 is central to the mechanism of action of, as well as prognostic and predictive to, PD-(L)1 immune checkpoint inhibition (ICI) therapy in non-small cell lung cancer (NSCLC). PD-L1 expression determined by immunohistochemistry (IHC), however, correlates moderately with patient survival and response to anti PD-(L)1 ICI. This discrepancy may be because of sampling errors from the spatial heterogeneity of tumor PD-L1 expression. Here we show that PD-L1 and PD-1 PET imaging can (1) visualize whole-body PD-(L)1 expression in patients with NSCLC, (2) specifically, revealing expression heterogeneity within tumors as well as among tumors within the same patient, and (3) demonstrate in vivo interactions between PD-L1 expression and anti PD-1 ICI, thus enhancing our understanding of tumor biology toward ICI.

Citation Format: David Leung. Whole-body PD-L1 and PD-1 PET: First-in-human experience [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA16.
Abstract IA17: AI-powered pathology for precision medicine
Authors: Beck Andrew H.
Published: March 2020

Pathologic analysis of patient tissue specimens plays a central role in the field of oncology. Recent advances in artificial intelligence and computer vision offer tremendous potential for discovering new pathologic mechanisms of cancer treatment response and identifying new diagnostics for matching patients and therapies. We will discuss these new advances and their potential for accelerating progress in the diagnosis and treatment of cancer, with a focus on immuno-oncology and therapies targeting the PD-1/PD-L1 pathway.

Citation Format: Andrew H. Beck. AI-powered pathology for precision medicine [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA17.
Abstract IA20: Chromatin state and scRNA-seq analysis defines a common differentiation trajectory towards T-cell exhaustion
Authors: Leslie Christina
Published: March 2020

We will describe a unified chromatin state and single cell expression analysis underlying T-cell differentiation to “exhaustion.” Numerous studies in chronic viral infection and tumor models have shown that most T cells progress to a terminally dysfunctional (“exhausted”) state from which they cannot be rescued by current immunotherapies. We performed a systematic analysis of over 280 ATAC-seq and RNA-seq experiments from eight published studies of CD8 T cell dysfunction, using a statistical batch correction to define a common differentiation trajectory to terminal exhaustion in all settings of chronic antigen exposure and to identify transcription factors involved in this progression. We further performed scRNA-seq analysis of CD8 T cells at multiple time points during acute and chronic viral infection and in adoptive cell transfer studies to elucidate this trajectory at single-cell resolution.

Citation Format: Christina Leslie. Chromatin state and scRNA-seq analysis defines a common differentiation trajectory towards T-cell exhaustion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA20.
Abstract IA23: The role of the microbiome in response and toxicity to cancer therapy
Authors: Wargo Jennifer A.
Published: March 2020

We have made tremendous progress in cancer care via the use of immunotherapy; however, not all patients respond and toxicity to therapy may be limiting. It is becoming increasingly clear that responses to therapy are dependent on a number of factors that influence tumor growth and immunity—and that these all are inter-related. There is a growing appreciation of the role of environmental factors, such as the microbiome, on responses to therapy. The microbiome refers to microbes and their genomes within a given host, and there is a significant contribution of microbes to our overall cellular content and to our genomic content. There is now evidence that the gut microbiome may shape immunity and responses to immunotherapy, and efforts are ongoing to modulate the microbiome to enhance therapeutic responses. Additionally, there is evidence that microbes within tumors of patients with cancer may shape responses to therapy. Furthermore, microbes may also influence toxicity to cancer therapy. The use of the microbiome as a biomarker and a therapeutic target will be discussed, as will complexities and recommendations for a path forward to implement microbiome analyses and targeting in precision cancer care and overall precision health.

Citation Format: Jennifer A. Wargo. The role of the microbiome in response and toxicity to cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA23.
Abstract PR11: Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses
Authors: Burger Megan L. , Crossland Grace E. , Schenkel Jason M. , Canner David A. , Jacks Tyler
Published: March 2020

In order to drive a productive T-cell response to checkpoint immunotherapy, tumors must be sufficiently antigenic. However, antigens vary in their degree of immunogenicity and consequently drive T-cell responses of different magnitudes and quality. In a genetically engineered mouse model of lung adenocarcinoma expressing model T-cell antigens, we find that antigen dominance hierarchies are established in tumors, where the T-cell response is largely focused on a dominant epitope as observed in viral infections. Interestingly, while T cells responding to a subdominant antigen are fewer in number, we find that they are less exhausted and express more markers of memory cells. T cells responding to the dominant antigen rapidly contract, while those responding to the subdominant antigen persist better over time. Despite their seemingly greater functional potential, T cells responding to the subdominant antigen fail to respond significantly to checkpoint immunotherapy in the context of this dominance hierarchy. Remarkably, removal of the dominant antigen unleashes the subdominant response and these cells expand to fill the effector niche previously occupied by the dominant response. Current experiments are testing the ability of vaccination to “break dominance” and improve the contribution of the subdominant response to tumor control. These findings could have great relevance to the design of personalized cancer vaccines, where targeting subdominant antigens over dominant antigens may lead to surprising therapeutic benefit.

This abstract is also being presented as Poster B36.

Citation Format: Megan L. Burger, Grace E. Crossland, Jason M. Schenkel, David A. Canner, Tyler Jacks. Antigen dominance hierarchies shape tumor T-cell phenotypes and immunotherapy responses [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR11.
Abstract PR12: Genomic landscape of immunotherapy resistance in lung cancer
Authors: Lau Denise , Stein Michelle , Perera Jason , Kannan Madhavi , Khan Aly
Published: March 2020

Immune checkpoint inhibitors (ICI) have emerged as an important modality in lung cancer treatment. However, studies have shown that only a fraction of patients will experience any clinical benefit when treated with ICI, and a better understanding of the mechanisms of resistance is still needed. In this study, we sought to characterize the prevalence of known mechanisms of primary and adaptive resistance in the context of the greater immunogenomic landscape in a real-world cohort of 100 non-small cell lung cancer patients treated with ICI. Targeted panel DNA sequencing and whole-transcriptome RNA sequencing were performed on a primary tumor biopsy for each patient, the clinical notes were abstracted and structured, and the digital image of the H&E was processed through a tumor-infiltrating lymphocyte (TIL) analysis pipeline. We evaluated each tumor for evidence of HLA loss of heterozygosity (LOH), mutations in the antigen presentation or interferon gamma signaling pathways, expression of alternative checkpoint molecules, and immune infiltrate exclusion. We found that over 25% of patients in the cohort showed signs of at least one of these mechanisms of ICI resistance. We evaluated the real-world progression-free survival (rwPFS) for these patients and found that the majority experienced a progression event within 6 months of treatment start. This study suggests that primary resistance to ICI affects a significant population of lung cancer patients.

This abstract is also being presented as Poster B22.

Citation Format: Denise Lau, Michelle Stein, Jason Perera, Madhavi Kannan, Aly Khan. Genomic landscape of immunotherapy resistance in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR12.
Abstract PR9: Loss of PD-1 promotes antitumor immunity by improving functions of both PD-1+ and PD-1- CD8+ T cells in the tumor microenvironment
Authors: Pauken Kristen E. , Juneja Vikram R. , Ringel Alison , Rowe Jared H. , Burke Kelly P. , Sage Peter T. , LaFleur Martin W. , Kuchroo Juhi R. , Ron-Harel Noga , Maleri Seth , Long Jaclyn M. , Freeman Gordon J. , Chevrier Nicolas , Haigis Marcia C. , Sharpe Arlene H.
Published: March 2020

Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates antitumor immunity are not fully understood. To determine PD-1 functions on different cell types, we used PD-1 conditional knockout mice. Subcutaneous transplantation of MC38 adenocarcinoma tumor cells in mice with complete deletion of PD-1 selectively on CD8+ T cells improved CD8+ T functions in the tumor microenvironment (TME). CD8+ T cells were required for the protective effects of PD-1 deletion in this model. To assess whether loss of PD-1 on all cells was necessary for improved antitumor immunity, we restricted PD-1 deletion to only half of the T-cell population. We hypothesized that a cell-intrinsic loss of PD-1 was necessary for improved T-cell fitness and effector functions. Here, deletion of PD-1 indeed led to T cell-intrinsic boosts in function. Unexpectedly, however, there was also a bystander effect that improved functions of PD-1-expressing CD8+ T cells in the TME. These data suggest that complete loss of PD-1 is not necessary for optimal tumor immunity, a finding that has important implications for applying PD-1-based immunotherapies to cancer patients.

This abstract is also being presented as Poster B82.

Citation Format: Kristen E. Pauken, Vikram R. Juneja, Alison Ringel, Jared H. Rowe, Kelly P. Burke, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Noga Ron-Harel, Seth Maleri, Jaclyn M. Long, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. Sharpe. Loss of PD-1 promotes antitumor immunity by improving functions of both PD-1+ and PD-1- CD8+ T cells in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR9.
Joint Effects of Body Mass Index and Waist Circumference on the Incidence of Hypertension in a Community-Based Chinese Population
Authors: Momin Mohetaboer , Fan Fangfang , Li Jianping , Jia Jia , Zhang Long , Zhang Yan , Huo Yong
Published: March 2020

Objective: We aimed to investigate the relationships of body mass index (BMI), waist circumference (WC), and obesity defined using a combination of both indexes, with the incidence of hypertension in a Chinese community-based population. Methods: A total of 1,927 Chinese participants (57.2 ± 8.9 years old) with normal blood pressure at baseline were recruited from the Shijingshan community in Beijing. Incident hypertension was defined as blood pressure ≥140/90 mm Hg, self-reported hypertension, or the use of any antihypertensive medication at the follow-up visit. Results: During 2.3 years of follow-up, 19.1% (n = 97) of the men and 13.6% (n = 158) of the women developed incident hypertension. The adjusted odds ratios (ORs) (95% confidence intervals [CIs]) for obesity (BMI ≥30) were 3.49 (1.59–7.66) and 2.60 (1.48–4.55) for men and women, respectively. A 1-point increase in BMI was associated with 8% (OR = 1.08, 95% CI: 1.00–1.17) and 10% (OR = 1.10, 95% CI: 1.05–1.16) increases in the incidence of hypertension in men and women, respectively. Abdominal obesity (WC ≥90 cm in men and ≥85 cm in women) was positively associated with incident hypertension in both men (adjusted OR = 1.79, 95% CI: 1.10–2.91) and women (adjusted OR = 1.61, 95% CI: 1.09–2.40). A 1-cm increase in WC was associated with 4% (adjusted OR = 1.04, 95% CI: 1.01–1.07) and 4% (adjusted OR = 1.04, 95% CI: 1.02–1.07) increases in the incidence of hypertension in men and women, respectively. The combination of abnormal BMI and WC has the highest risk for hypertension in both men (adjusted OR = 3.10, 95% CI: 1.48–6.50) and women (adjusted OR = 2.51, 95% CI: 1.43–4.40). Conclusions: This study shows that BMI, WC, and an index that combined the two are independently associated with incident hypertension in a Chinese community-based population.
A Technical Tip to Avert Meniscal Rotation and Dislocation in a Mobile Bearing Unicompartmental Knee Arthroplasty
Authors: Kumar Vijay , Nayak Mayur , Panthee Rajan , Yadav Rahul , Marendupaka Siddhartha
Published: March 2020

The Oxford (Oxford® partial knee; Biomet) mobile bearing medial unicondylar knee replacement (OUKR) is a preferred choice by surgeons due to minimal blood loss, reduced pain, and better range of motion. Commonly observed complications include aseptic loosening, polyethylene wear, bearing dislocation, and periprosthetic fractures. A bearing dislocation can be prevented by ensuring that there is correct tracking of bearing during the trial reduction as well as no loss of entrapment. We present a case report in a 50-year-old patient undergoing bilateral OUKR wherein it was observed that the meniscal bearing upon the flexion of the knee joint had the tendency to dislocate. Upon revising the vertical tibial recut according to the anterior superior iliac spine, the meniscus was found to have a normal excursion. Mobile bearing dislocation is a unique complication of mobile bearing OUKR. Surgical technique is of paramount importance in ensuring a successful OUKR. The vertical tibial cut is made to accommodate the vertical wall of the tibial component. Meniscal displacement is quite a common complication and can occur due to multiple causes. Inaccurate vertical tibial cut may be one such reason leading to tibial dislocation.
Application of Fluorescent Dyes in Visceral Surgery: State of the Art and Future Perspectives
Authors: Nowak Kai , Karampinis Ioannis , Gerken Andreas Lutz Heinrich
Published: March 2020

Background: Through the improvement and implementation of advanced intraoperative imaging, the indications for intraoperative fluorescence have spread to various fields of visceral surgery. Indocyanine green (ICG)-based fluorescence angiography and the imaging systems using this certain dye are currently the cornerstone of intraoperative, fluorescence-based medical imaging. Summary: The article focuses on principles and approaches of intraoperative fluorescence in general surgery. The current clinical practice of intraoperative fluorescence and its evidence are described. Emerging new fields of application are put in a perspective. Furthermore, the technique and possible pit-falls in the performance of intraoperative ICG fluorescence angiography are described in this review article. Key Messages: Overall growing evidence suggests that intraoperative fluorescence imaging delivers valuable additional information to the surgeon, which might help to perform surgery more exactly and reduce perioperative complications. Perfusion assessment can be a helpful tool when performing critical anastomoses. There is evidence from prospective and randomized trials for the benefit of intraoperative ICG fluorescence angiography during esophageal reconstruction, colorectal surgery, and surgery for mesenteric ischemia. Most studies suggest the administration of 2.5–10 mg of ICG. Standardized settings and documentation are essential. The benefit of ICG fluorescence imaging for gastrointestinal sentinel node detection and detection of liver tumors and colorectal metastases of the liver cannot clearly be estimated duo to the small number of prospective studies. Critical points in the use of intraoperative fluorescence imaging remain the low standardization and reproducibility of the results and the associated difficulty in comparing the results of the existing trials. Furthermore, little is known about the influence of hemodynamic parameters on the quantitative assessment of ICG fluorescence during surgery.
Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa
Authors: Menghini Moreno , Jolly Jasleen K. , Nanda Anika , Wood Laura , Cehajic-Kapetanovic Jasmina , MacLaren Robert E.
Published: March 2020

Introduction: Introduction of retinal gene therapy requires established outcome measures along with thorough understanding of the pathophysiology. Evidence of early, thinned outer segments in RPGR X-linked retinitis pigmentosa could help understand how the level of cone photoreceptor involvement translates to visual potential. Objective: Analysis of foveal photoreceptor outer segment length in a young cohort of RPGR patients to help clarify the reason for absent maximal visual acuity seen. Methods: Case-control study of RPGR patients. Quantitative measurement of photoreceptor outer segment by OCT. Results: Eighteen male RPGR patients and 30 normal subjects were included. Outer segment thickness differed significantly between the RPGR and normal eyes (p < 0.0005). Mean outer segment values were 35.6 ± 2.3 µm and 35.4 ± 2.6 µm for RPGR right and left eyes, respectively. In normal eyes, the mean outer segment thickness was 61.4 ± 0.7 µm for right eyes and 62.4 ± 0.7 µm for left eyes. Conclusions: Patients with RPGR X-linked retinitis pigmentosa show thinning of the foveal photoreceptor outer segment thickness early in the disease course, which could be an explanation for the lower maximum visual acuity seen. These findings must be taken into consideration when assessing efficacy outcome measures in retinal gene therapy trials.
Rediscovery of Epilobium trichophyllum Hausskn.: a rare and endemic plant from Sikkim Himalaya, India
Authors: Biate David L. , Agrawala Dinesh K.
Published: March 2020

Epilobium trichophyllum Hausskn., is a rare and endemic plant known only from its type collection [Sikkim (10-12000 ft.), Latung (Lachung), 13.vii.1849, J.D. Hooker & Thomson 7 (K- Royal Botanic Garden, Kew; W - Naturhistorisches Museum Wien, Vienna)].   An unidentified specimen at BSHC [Pradhan & Giri 29191A (BSHC!)] with characteristic villous hairs throughout the plant could be determined as Epilobium trichophyllum Hausskn.  This specimen was collected in 2006 (after a gap of 157 years) from Zema-1 on the way from Lachen to Thangu with similar phyto-climatic condition as that of the type locality.  A brief description, taxonomic history and photograph of the specimens have been provided to confirm its identity.  Its threat status has been assessed as ‘Critically Endangered’ as per IUCN Red List criteria.
New records of Heloderma alvarezi (Wiegmann, 1829) (Sauria: Helodermatidae) on the coast of Oaxaca and increases to its distribution in Mexico
Authors: Garcia-Grajales Jesús , Arrazola Bohórquez Rodrigo , Penguilly Macías María Arely , Buenrostro Silva Alejandra
Published: March 2020

This work provides three new photographic records and evidence of increase in distribution of Heloderma alvarezi based on different encounters between human activities and the displacement of this species along the central coast of Oaxaca, Mexico.  Until now, this species occurred only in Chiapas State, however, the new records provide information about the increase in species distribution on the coast of Oaxaca, so this has increased the number of reptiles in Oaxaca to 448 species.
Runx2 (Runt-Related Transcription Factor 2)-Mediated Microcalcification Is a Novel Pathological Characteristic and Potential Mediator of Abdominal Aortic Aneurysm
Authors: Li Zhiqing , Zhao Zuoquan , Cai Zeyu , Sun Yong , Li Li , Yao Fang , Yang Liu , Zhou Yuan , Zhu Haibo , Fu Yi , Wang Li , Fang Wei , Chen Yabing , Kong Wei
Published: March 2020

Objective:

Abdominal aortic aneurysms (AAAs) are highly lethal diseases without effective clinical predictors and therapeutic targets. Vascular microcalcification, as detected by fluorine-18-sodium fluoride, has recently been recognized as a valuable indicator in predicting atherosclerotic plaque rupture and AAA expansion. However, whether vascular microcalcification involved in the pathogenesis of AAA remains elusive.

Approach and Results:

Microcalcification was analyzed in human aneurysmal aortas histologically and in AngII (angiotensin II)-infused
ApoE
−/−
mouse aortas by fluorine-18-sodium fluoride positron emission tomography and X-ray computed tomography scanning in chronological order in live animals. AAA patients’ aortic tissue showed markedly enhanced microcalcification in the aortic media within the area proximal to elastic fiber degradation, compared with non-AAA patients. Enhanced fluorine-18-sodium fluoride uptake preceded significant aortic expansion in mice. Microcalcification-positive mice on day 7 of AngII infusion showed dramatic aortic expansion on subsequent days 14 to 28, whereas microcalcification-negative AngII-infused mice and saline-induced mice did not develop AAA. The application of hydroxyapatite, the main component of microcalcification, aggravated AngII-induced AAA formation in vivo. RNA-sequencing analysis of the suprarenal aortas of 4-day-AngII–infused
ApoE
−/−
mice and bioinformatics analysis with ChIP-Atlas database identified the potential involvement of the osteogenic transcriptional factor Runx2 (runt-related transcription factor 2) in AAA. Consistently, vascular smooth muscle cell–specific Runx2 deficiency markedly repressed AngII-induced AAA formation in the
ApoE
−/−
mice compared with the control littermates.

Conclusions:

Our studies have revealed microcalcification as a novel pathological characteristic and potential mediator of AAA, and targeting microcalcification may represent a promising strategy for AAA prevention and treatment.
Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease
Authors: Gupta Nilaksh , Buffa Jennifer A. , Roberts Adam B. , Sangwan Naseer , Skye Sarah M. , Li Lin , Ho Karen J. , Varga John , DiDonato Joseph A. , Tang W.H. Wilson , Hazen Stanley L.
Published: March 2020

Objective:

Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited.

Approach and Results:

Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment.

Conclusions:

Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.
Appropriateness of Transcatheter Aortic Valve Replacement
Authors: Inohara Taku , Vemulapalli Sreekanth , Kohsaka Shun , Yashima Fumiaki , Watanabe Yusuke , Shirai Shinichi , Tada Norio , Araki Motoharu , Naganuma Toru , Yamanaka Futoshi , Ueno Hiroshi , Tabata Minoru , Mizutani Kazuki , Higashimori Akihiro , Takagi Kensuke , Yamamoto Masanori , Shimizu Hideyuki , Fukuda Keiichi , Hayashida Kentaro ,   On behalf of the OCEAN-TAVI Investigators
Published: March 2020

Background:

Transcatheter aortic valve replacement (TAVR) is widely used; however, its appropriateness is unknown. We sought to investigate the appropriateness of TAVR.

Methods and Results:

We assigned appropriateness ratings to patients undergoing TAVR for severe aortic stenosis between October 2013 and May 2017 at 14 Japanese hospitals participating in the optimized transcatheter valvular intervention-transcatheter aortic valve implantation registry according to the US appropriate use criteria for treating severe aortic stenosis. To account for the influence of uncaptured variables on appropriate use criteria ratings, we initially assigned them to a best-case scenario where they were assumed to classify a case to the most appropriate clinical scenario and then to a worst-case scenario where assumed least appropriate. Overall proportion of TAVRs classified as appropriate, maybe appropriate, or rarely appropriate was assessed. In addition, extent of hospital-level variation in rarely appropriate procedures was evaluated. Of 2036 TAVRs (median age [25th, 75th]: 85.0 years [81.0–88.0]; 70.5% female the Society of Thoracic Surgeons Predicted Risk of Mortality score: 6.2% [4.4–8.9]), in the best-case scenario, 177 (8.7%) were not successfully mapped, and 1580 (77.6%) were classified as appropriate, 180 (8.8%) as maybe appropriate, 99 (4.9%) as rarely appropriate, respectively. In the worst-case scenario, the rate of rarely appropriate increased to 6.8%. The majority of rarely appropriate TAVRs was performed in patients with moderate to severe dementia (defined as mini-mental status examination of ≤17), bicuspid aortic valve, or anticipated life expectancy <1 year. There was substantial variation in the proportion of rarely appropriate TAVR across hospitals (median rate of rarely appropriate: 4.9% [3.8–6.6] in the best-case scenario,
P
<0.001; 6.5% [5.6–8.6] in the worst-case scenario,
P
<0.001).

Conclusions:

In clinical practice, the proportion of rarely appropriate TAVRs ranged from 4.9% to 6.8% with substantial institutional variation. Our study elucidates common clinical scenarios deemed rarely appropriate and clarifies the potential targets of quality improvement.

Registration:

URL:
https://www.umin.ac.jp/ctr/index.htm
. Unique identifier: UMIN000020423.
Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy
Authors: Wallace Kendall B. , Sardão Vilma A. , Oliveira Paulo J.
Published: March 2020

Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.
Cold-Inducible RNA-Binding Protein Prevents an Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase
Authors: Xie Duanyang , Geng Li , Xiong Ke , Zhao Tingting , Wang Shuo , Xue Jinfeng , Wang Cheng , Wang Guanghua , Feng Zhiqiang , Zhou Huixing , Li Yini , Li Li , Liu Yi , Xue Zhigang , Yang Jian , Ma Honghui , Liang Dandan , Chen Yi-Han
Published: March 2020

Rationale:

The stress response of heart rate, which is determined by the plasticity of the sinoatrial node (SAN), is essential for cardiac function and survival in mammals. As an RNA-binding protein, CIRP (cold-inducible RNA-binding protein) can act as a stress regulator. Previously, we have documented that CIRP regulates cardiac electrophysiology at posttranscriptional level, suggesting its role in SAN plasticity, especially upon stress conditions.

Objective:

Our aim was to clarify the role of CIRP in SAN plasticity and heart rate regulation under stress conditions.

Methods and Results:

Telemetric ECG monitoring demonstrated an excessive acceleration of heart rate under isoprenaline stimulation in conscious CIRP-KO (knockout) rats. Patch-clamp analysis and confocal microscopic Ca
2+
imaging of isolated SAN cells demonstrated that isoprenaline stimulation induced a faster spontaneous firing rate in CIRP-KO SAN cells than that in WT (wild type) SAN cells. A higher concentration of cAMP—the key mediator of pacemaker activity—was detected in CIRP-KO SAN tissues than in WT SAN tissues. RNA sequencing and quantitative real-time polymerase chain reaction analyses of single cells revealed that the 4B and 4D subtypes of PDE (phosphodiesterase), which controls cAMP degradation, were significantly decreased in CIRP-KO SAN cells. A PDE4 inhibitor (rolipram) abolished the difference in beating rate resulting from CIRP deficiency. The mechanistic study showed that CIRP stabilized the mRNA of
Pde4b
and
Pde4d
by direct mRNA binding, thereby regulating the protein expression of PDE4B and PDE4D at posttranscriptional level.

Conclusions:

CIRP acts as an mRNA stabilizer of specific PDEs to control the cAMP concentration in SAN, maintaining the appropriate heart rate stress response.
Exercise Capacity, Coronary Artery Fatty Plaque, Coronary Calcium Score, and Cardiovascular Events in Subjects With Stable Coronary Artery Disease
Authors: Malik Abdulaziz , Kanduri Jaya S. , Asbeutah Abdul Aziz A. , Khraishah Haitham , Shen Changyu , Welty Francine K.
Published: March 2020

Background

Aerobic exercise capacity is inversely associated with cardiovascular and all‐cause mortality in men and women without coronary artery disease (
CAD
); however, a higher amount of vigorous exercise is associated with a J‐shaped relationship in
CAD
patients. Therefore, the optimal type and amount of exercise for
CAD
patients is unclear. Coronary artery calcification (
CAC
) is associated with increased cardiovascular disease (
CVD
) events and mortality. Fatty plaque is more likely to rupture and cause coronary events than other types. We examined the association between exercise capacity, fatty plaque,
CAC
score and
CVD
events in
CAD
patients.

Methods and Results

A total of 270 subjects with stable
CAD
were divided into tertiles based on metabolic equivalents of task (
MET
s) calculated from exercise treadmill testing. Self‐reported exercise was obtained. Coronary computed tomographic angiography measured coronary plaque volume and
CAC
score. After adjustment, fatty plaque volume was not different among the 3
MET
groups. For each 1
MET
increase,
CAC
was 66.2 units lower (
P
=0.017). Those with
CAC
>400 and ≥8.2
MET
s had fewer
CVD
events over 30 months compared to <8.2
MET
s (
P
=0.037). Of moderate intensity exercisers (median, 240 min/wk; 78% walking only), 62.4% achieved ≥8.2
MET
s and lower
CAC
scores (
P
=0.07). Intensity and duration of exercise had no adverse impact on coronary plaque or
CVD
events.

Conclusions

Achieving ≥8.2
MET
s with moderate exercise intensity and volume as walking resulted in lower
CAC
scores and fewer
CVD
events. Therefore, vigorous exercise intensity and volume may not be needed for
CAD
patients to derive benefit.

Registration

URL
:
https://www.clinicaltrials.gov
; Unique Identifier:
NCT
01624727.
Clinical Potential of Targeting Fibroblast Growth Factor‐23 and αKlotho in the Treatment of Uremic Cardiomyopathy
Authors: Law Jonathan P. , Price Anna M. , Pickup Luke , Radhakrishnan Ashwin , Weston Chris , Jones Alan M. , McGettrick Helen M. , Chua Winnie , Steeds Richard P. , Fabritz Larissa , Kirchhof Paulus , Pavlovic Davor , Townend Jonathan N. , Ferro Charles J.
Published: March 2020

Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor‐23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor‐23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end‐stage renal disease.
Four Beasts and a Baby
Authors: Djurslev Christian Thrue
Published: March 2020

The present article hypothesizes that a bizarre omen story of Alexander’s death belongs in a Hellenistic literary context rather than a historical Babylonian one. Several texts, including the Greek Alexander Romance (3.30), relate the birth omen of a stillborn child with living animals for his lower body. The court of Alexander decides to burn the portent. I suggest that the omen should be read as a manifestation of a teras in the Greek paradigm. In support of this argument, I offer comparable evidence from numerous sources, including iconographical material and the animal prophecies, primarily from the Old Testament Book of Daniel. The article ends with some thoughts on how this teras interpretation of the omen story exposes the tale as a Hellenistic construct.
Two species of nivicolous myxomycetes that formed fruiting bodies during three spring seasons in the lowlands of the Eastern Ukraine

Authors: YATSIUK IRYNA , LEONTYEV DMITRY
Published: March 2020

Two species of nivicolous myxomycetes, Lamproderma pseudomaculatum and Lamproderma aff. pulchellum, previously considered as strictly montane, are reported from the lowlands (116–192 m a.s.l.) of the eastern Ukraine during three spring seasons. Lowland collections of L. aff. pulchellum show comparatively low genetic similarity with specimens of this species collected at high elevations and may represent a new taxon. Autumn frosts, which occurred before the formation of a stable snow cover, as well as the limited number of days with snow cover exceeding 30 cm, did not prevent the abundant fruiting of these myxomycetes.
NOVELTIES IN BRAZILIAN BEGONIACEAE II: a new species from Minas Gerais

Authors: KOLLMANN LUDOVIC JEAN CHARLES
Published: March 2020

Begonia vasconselosiana, a new species of Begonia from Minas Gerais state, Brazil is described. Begonia vasconselosiana is morphologically similar to Begonia lealii Brade with which it is compared. The new species grows in campos rupestres in Atlantic Forest, east of Minas Gerais state, Brazil. Description, diagnosis, etymology, taxonomic comments, illustrations, and conservation status of the new species are provided.