bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA24: Immune-modulating approaches to cancer therapy: Focusing on combinations
Authors: Wolchok Jedd 
Published: June 2021

Abstract
Given the activity noted with both CTLA-4 or PD-1 blockade, clinical trials are now investigating combination checkpoint blockade. The most mature data with a combination of ipilimumab + nivolumab in melanoma showed a response rate of 60% in the context of increased yet manageable toxicity. Such responses are generally durable, even when treatment was stopped early for toxicity. Unlike in studies of PD-1 blockade monotherapy, there was no significant difference in clinical activity based on tumor expression of PD-L1. This approach has gained regulatory approval for metastatic melanoma and is in late-stage clinical trials for other malignancies. Attention is being paid to the reasons underlying the efficacy of checkpoint blockade in certain malignancies. One hypothesis has been that cancers having a high mutational load may be more amenable to immune modulation by virtue of the larger number of potential neoepitopes present, fostering baseline immune recognition that can then be potentiated by checkpoint blockade. We have found that melanoma patients having long-term clinical activity with ipilimumab have a significantly greater median number of nonsynonymous passenger mutations, compared with patients who do not respond or those who have only short-term regression. Strategies to enhance baseline immune reactivity are therefore necessary to investigate as a means to improve the impact of checkpoint blockade on a broad spectrum of cancers. The presence of suppressive myeloid cells in the tumor microenvironment also is emerging as a mechanism of resistance to the antitumor activity for checkpoint blockade. Strategies to overcome this include inhibition of CSF-1R signaling, IDO activity, and selective suppression of PI3K-γ.
Citation Format: Jedd Wolchok. Immune-modulating approaches to cancer therapy: Focusing on combinations [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA24.
Abstract IA25: Control of tumor immune suppression by macrophage PI3Kγ regulated pathways
Authors: Varner Judith A. 
Published: June 2021

Abstract
Macrophages play key roles in promoting immune suppression, tumor growth, and resistance to therapy. Our recent studies show that tissue-resident macrophages (TRM) as well as bone marrow-derived macrophages (BMDM) play critical but unique roles in promoting tumor growth. While BMDM are recruited to tumors in a PI3Kγ, Integrin α4, and CCR2-dependent manner, TRMs accumulate in tumors independently of integrin α4, PI3Kγ, or the trafficking receptor CCR2. Gene expression and functional studies indicate that tumor-derived TRM are highly proliferative, immune suppressive, and distinct from BMDM. We show that TRM develop from macrophage progenitors that are abundant in tumors but not in normal tissues; purified progenitors differentiate into macrophages that potently stimulate tumor growth when adoptively transferred into mice. Notably, we found that the lipid kinase PI3Kγ promotes immune-suppressive polarization of TRM and BMDM. Inhibition of PI3Kγ repolarizes macrophages, induces dendritic cell maturation, and stimulates CD8+ T-cell recruitment to tumors and activation. Inhibition of PI3Kγ also synergizes with checkpoint inhibitors and chemotherapeutics to promote tumor regression and immunologic memory, leading to sustained tumor suppression. Our studies identify PI3Kγ as a valuable target for immune therapy of solid tumors.
Citation Format: Judith A. Varner. Control of tumor immune suppression by macrophage PI3Kγ regulated pathways [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA25.
Abstract PR04: Single-cell analysis illuminates dysfunctional CD8+ T cells as a proliferative, dynamically regulated compartment within human melanoma
Authors: Yofe Ido , Li Hanjie , van der Leun Anne , Lubling Yaniv , Solodkin Dikla Gelbard , van Akkooi Alexander , Horlings Hugo M. , David Eyal , Baran Yael , Berkovitz Akihad , Lifshitz Aviezer , Schumacher Ton N. , Tanay Amos , Amit Ido 
Published: June 2021

Abstract
The immune cell composition within tumors plays a major role in response to immunotherapy. Therefore, comprehensive characterization of the diverse functional states exhibited by immune cell infiltrates, and their association with treatment outcome, is critical for the development of more effective immunotherapies. We combined single-cell RNA- and TCR-sequencing with an autologous tumor reactivity assay, tracing immune cell heterogeneity and dynamics in melanoma patients. Analysis of 70,000 cells revealed the presence of two effector T-cell subsets, of which only one transitions into a dysfunctional T-cell population, as based both on TCR sharing as well as a gradient of expression of dysfunction-associated genes present in virtually all samples. Notably, we denote dysfunctional T cells— and in particular early dysfunctional cells—as the major proliferating immune cell compartment. Furthermore, TCR-seq of autologous tumor reactive T cells illustrated that presence of reactive potential is associated with the magnitude of dysfunctional signature and is in concordance with response to immunotherapy. Data from 25 melanoma patients confirm the universality of these observations and distinguish shared and divergent regulatory modules between dysfunctional CD8 and regulatory T cells. Our analysis also puts forward novel candidate genes, which are highly correlated with known checkpoint targets within specific cellular subsets and may prove to be effective targets for checkpoint blockade. In conclusion, our findings proclaim that CD8 T cells previously associated with a dysfunctional or exhausted state are in fact a highly proliferating and dynamically interacting cell population within the human tumor microenvironment.
This abstract is also being presented as Poster B58.
Citation Format: Ido Yofe, Hanjie Li, Anne van der Leun, Yaniv Lubling, Dikla Gelbard Solodkin, Alexander van Akkooi, Hugo M. Horlings, Eyal David, Yael Baran, Akihad Berkovitz, Aviezer Lifshitz, Ton N. Schumacher, Amos Tanay, Ido Amit. Single-cell analysis illuminates dysfunctional CD8+ T cells as a proliferative, dynamically regulated compartment within human melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR04.
Abstract PR05: Blockade of AHR activation by IDO/TDO-derived kynurenine restricts cancer immune suppression
Authors: Campesato Luis F. , Budhu Sadna , Gigoux Mathieu , Tchaicha Jeremy , Pourpe Stephane , Liu Cailian , Zamarin Dmitriy , Manfredi Mark G. , McGovern Karen , Wolchok Jedd D. , Merghoub Taha 
Published: June 2021

Abstract
Immune checkpoint blockade (ICB) has been shown to convey significant clinical activity across a spectrum of malignancies, yet there is now recognition that multiple mechanisms of resistance can impair response. The catabolism of tryptophan into metabolites known as kynurenines (Kyn) by enzymes such as indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO) plays a major suppressive role. Recently it was shown that Kyn acts as an endogenous agonist of the Aryl hydrocarbon receptor (AhR). In order to gain a better understanding of this pathway, we sought to characterize the mechanisms of immunosuppression associated with AhR and evaluate its potential as therapeutic target. Gene-expression analysis of IDO-overexpressing melanomas (B16-IDO vs. B16-WT) demonstrated reduced expression levels of Type 1 inflammatory genes, including IFNy, TNF, GzmB, and CD40. In addition, B16-IDO presents higher infiltration of tumor-associated macrophages TAMs, which upregulate the AHR as well as classic AhR-regulated genes (Cyp1a1 and Cyp1b1) and are differentially skewed towards an immunosuppressive M2 phenotype. Tumor-antigen specific CD8+T cells show reduced expression of activation markers (GzmB and CD44) and proliferation rate when primed by Kyn-treated antigen-presenting cells. In addition, TAMs from B16-IDO tumors suppressed activation of CD8+T cells in vitro and their depletion delayed tumor growth. When B16-IDO cells are implanted in mice depleted of Foxp3 expressing cells, TAMs do not accumulate. Treatment of B16-IDO tumors with an AhR-specific antagonist (CH-223191) upregulates MHC II in APCs, activation markers in CD8s, and reduced frequency of T-regs in B16-IDO tumors. AhR inhibition slows tumor growth and prolongs survival of tumors with active IDO/TDO/Kyn pathway (B16-IDO and B16-TDO), and this is enhanced when PD-1 blockade is used in combination. In summary, our findings demonstrate that targeting the Kyn pathway through AhR inhibition could overcome key suppressive mechanisms and sensitize tumors to ICB.
This abstract is also being presented as Poster A57.
Citation Format: Luis F. Campesato, Sadna Budhu, Mathieu Gigoux, Jeremy Tchaicha, Stephane Pourpe, Cailian Liu, Dmitriy Zamarin, Mark G. Manfredi, Karen McGovern, Jedd D. Wolchok, Taha Merghoub. Blockade of AHR activation by IDO/TDO-derived kynurenine restricts cancer immune suppression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR05.
Abstract PR22: Collagen scavenging alters macrophage phenotype in pancreatic cancer
Authors: LaRue Madeleine M. , Cullis Jane , Bar-Sagi Dafna 
Published: June 2021

Abstract
A hallmark of pancreatic tumors is their highly desmoplastic stroma composed of fibroblasts, immune cells and a dense network of collagen fibers. Pancreatic tumor-associated macrophages are considered M2 macrophages and are thought to support tumor progression through the engagement of multiple mechanisms that promote immune tolerance. Another well-documented role of M2 macrophages is the remodeling of the tumor stroma via collagen production and degradation, with the latter being mediated by mannose receptor (Mrc1)-mediated endocytosis of collagen. Given our previous work showing that protein scavenging by tumor cells can be utilized as a nutrient delivery mechanism, we set out to investigate the functional significance of collagen scavenging by macrophages. We have found that, in M2 macrophages, Mrc1-mediated collagen internalization and subsequent lysosomal degradation leads to a metabolic reprogramming that is characterized by the accumulation of collagen-derived intracellular free amino acids and an increase in arginine biosynthesis. The increase in arginine levels results in a significant upregulation of inducible nitric oxide synthase (iNOS) and arginase 1 (ARG1), giving rise to an M1/M2 hybrid macrophage. Moreover, iNOS+ARG1+ double-positive macrophages are present in the microenvironment of pancreatic tumors. The functional contribution of this cell population to pancreatic tumorigenesis is being investigated. Our findings suggest a new modality for the functional modulation of tumor-associated macrophages through the coupling of extracellular matrix remodeling to protein scavenging.
This abstract is also being presented as Poster A58.
Citation Format: Madeleine M. LaRue, Jane Cullis, Dafna Bar-Sagi. Collagen scavenging alters macrophage phenotype in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR22.
Demographic Disparities in Proximity to Certified Stroke Care in the United States
Authors: Yu Cathy Y. , Blaine Timothy , Panagos Peter D. , Kansagra Akash P. 
Published: June 2021

Background and Purpose:
Demographic disparities in proximity to stroke care influence time to treatment and clinical outcome but remain understudied at the national level. This study quantifies the relationship between distance to the nearest certified stroke hospital and census-derived demographics.

Methods:
This cross-sectional study included population data by census tract from the United States Census Bureau’s 2014–2018 American Community Survey, stroke hospitals certified by a state or national body and providing intravenous thrombolysis, and geographic data from a public mapping service. Data were retrieved from March to November 2020. Quantile regression analysis was used to compare relationships between road distance to the nearest stroke center for each census tract and tract-level demographics of age, race, ethnicity, medical insurance status, median annual income, and population density.

Results:
Two thousand three hundred eighty-eight stroke centers and 71 929 census tracts including 316 995 649 individuals were included. Forty-nine thousand nine hundred eighteen (69%) tracts were urban. Demographic disparities in proximity to certified stroke care were greater in nonurban areas than urban areas. Higher representation of individuals with age ≥65 years was associated with increased median distance to a certified stroke center in nonurban areas (0.51 km per 1% increase [99.9% CI, 0.42–0.59]) but not in urban areas (0.00 km [−0.01 to 0.01]). In urban and nonurban tracts, median distance was greater with higher representation of American Indian (urban: 0.10 km per 1% increase [0.06–0.14]; nonurban: 1.06 km [0.98–1.13]) or uninsured populations (0.02 km [0.00–0.03]; 0.27 km [0.15–0.38]). Each $10 000 increase in median income was associated with a decrease in median distance of 5.04 km [4.31–5.78] in nonurban tracts, and an increase of 0.17 km [0.10–0.23] in urban tracts.

Conclusions:
Disparities were greater in nonurban areas than in urban areas. Nonurban census tracts with greater representation of elderly, American Indian, or uninsured people, or low median income were substantially more distant from certified stroke care.
Evaluation of Medications Used for Hospitalized Patients With Sleep Disturbances: A Frequency Analysis and Literature Review
Authors: White Brittany , Snyder Heather S. , Patel Megan Van Berkel 
Published: June 2021

Purpose: Poor sleep during hospitalization is common and implicated in worse patient outcomes. Despite implementation of non-pharmacologic techniques, medications are still frequently required. The study objective is to assess the frequency of new medications administered for sleep in hospitalized patients and to review literature evaluating these drug therapies in the inpatient setting. Methods: This retrospective study included adult inpatients if they received a new medication for sleep during a 5-day period. Patients were excluded if the medication was continued from home or if sleep was not the documented indication. For the literature review, a MEDLINE search was conducted to identify studies pertaining to pharmacotherapy for sleep in hospitalized patients. Results: Of 1,968 patient-days reviewed, a medication for sleep was given for 166 patient-days (8.4%) in 78 patients. Melatonin was most commonly received (70.5%), followed by benzodiazepines (9.6%). A review of antihistamines, benzodiazepines, melatonin, quetiapine, trazodone, and Z-drugs (non-benzodiazepine hypnotics) was conducted and 23 studies were included. Conclusions: Despite widespread use of pharmacotherapy for sleep, there is a paucity of data evaluating use in the inpatient setting. Although there is significant heterogeneity among studies, melatonin has the strongest evidence for use and is an attractive option given its lack of adverse reactions and drug interactions. Benzodiazepines and Z-drugs were also frequently utilized; however, their reduced clearance in the elderly and potential for compounded sedative effects should be weighed heavily against potential sleep benefits. Antipsychotic agents cannot be recommended for routine use due to limited data and the potential for significant adverse effects.
Mixed and single gas permeation performance analysis of amino-modified ZIF based mixed matrix membrane
Authors: Salahuddin Zarrar , Farrukh Sarah , Hussain Arshad , Noor Tayyaba , Kwapinski Witold 
Published: June 2021

Dense and translucent CA/PEG 1000/ZIF membranes were synthesized in acetone, utilizing solution casting. Membrane characterization was carried out using FT-IR, SEM and tensile testing. SEM proved presence of dense membranes and increase in the filler amount may have formed voids, raising the permeability of both gases. Single and mixed gas (CO2/CH4) permeation testing showed an increased permeability, on addition of more filler, which is probably due to formation of nano-gaps. A maximum selectivity of 39.49 and 34.86 for single and mixed gases respectively, and maximum permeabilities of 49.7685 and 1.41 barrers were observed. Tensile testing showed that strength peaked then decreased on increased loading, due to agglomeration on adding more ZIF, which introduced defects in structure. To conclude, selectivity of higher loaded membranes is favourable whereas tensile strength of lower loaded membrane is superior, but we have a trade-off between selectivity and tensile strength, so a higher-loaded membrane is most suitable. [Formula: see text]
An Interprofessional Approach to Advance Care Planning
Authors: Kwak Jung , Jamal Aleena , Jones Barbara , Timmerman Gayle M. , Hughes Brian , Fry Liam 
Published: June 2021

Context: Advance care planning (ACP) can improve patients’ outcomes at end of life, and interprofessional collaboration has been recommended to facilitate ACP. However, role confusion in ACP facilitation among team members from different disciplines exists, and health professional disciplines’ expectations for interprofessional collaboration in ACP are unclear. Objective: To review expectations of major health professional organizations for ACP competencies, in order to identify gaps and opportunities for promoting interprofessional collaboration in ACP facilitation. Methods: Guidelines and recommendations for ACP across disciplines including chaplaincy, medicine, nursing, psychology, and social work were identified and analyzed using content analysis. Main themes were then reviewed against national consensus statements on 4 ACP outcomes (process outcomes, action outcomes, quality of care outcomes, and healthcare outcomes) and mapped into existing domains for interprofessional education competency: values/ethics, roles/responsibilities, interprofessional communication, and teams and teamwork. Results: Three major content themes were identified: professional commitment to advocating for patients’ values and self-determination, professional responsibility to facilitate ACP, and specific tasks in ACP. These themes addressed mostly process and action outcomes of ACP but not quality of care outcomes or healthcare outcomes. Few disciplines included interprofessional collaboration as part of ACP competency. Conclusion: There is a need for standardized competency guidelines for interprofessional collaboration in ACP as an important first step in reducing confusion among roles and other challenges in facilitating ACP. Further efforts in practice, research, and policy are needed to facilitate interprofessional ACP, achieve competencies, and improve patients’ outcomes.
Orbital neuromuscular choristoma of the ophthalmic nerve
Authors: Bermudez-Castellanos Irene , Marques-Fernandez Victoria , Gonzalez-Gonzalez Diego , Alvarez-Garcia Marta , Galindo-Ferreiro Alicia 
Published: June 2021

Introduction: Neuromuscular choristoma (NC) is a rare tumor composed of striated muscle fibers admixed with nerve fibers that often affects large peripheral nerve trunks in children. To the best of our knowledge, this is the first reported case in the literature of a NC of the ophthalmic nerve in an adult. Case description: A 27-year-old woman presented with a 20-day history of left periorbital headache radiating to the frontotemporal region, with associated tearing, nausea, and vomiting. The examination was normal, except for hypoesthesia in the distribution of the first trigeminal nerve branch (V1). Cranial computerized tomography showed a lesion in the left orbit and cavernous sinus with widening of the superior orbital fissure. On magnetic resonance imaging, the lesion was well-defined with fusiform morphology and showed a central cystic component and peripheral enhancement. An extradural approach was performed with subtotal tumor resection. Biopsy showed proliferation of striated muscle cells admixed with nerve fascicles and Schwann cells. A pathological diagnosis of NC of V1 was determined. Six months after surgery, left hypotropia with limitation of supraduction was observed, as well as hypoesthesia and paralysis of the left forehead with ipsilateral eyebrow ptosis. The rest of the examination remained within normal limits. Conclusion: NC should be considered in the differential diagnosis of a young patient with periorbital headache and hypoesthesia in the V1 region.
Point Blank: A Retrospective Review of Self-inflicted Gunshot Wounds to the Hand
Authors: Starr Brian W. , Dembinski Douglas R. , Yuan Frank , Lax Elizabeth A. , Yalamanchili Suma , Megee David M. 
Published: June 2021

Background A paucity of literature exists specifically examining self-inflicted (SI) gunshot wounds (GSWs) to the hand and wrist, which impart greater energy and have a higher risk of adverse events than non–self-inflicted (NSI) GSWs. Methods We retrospectively reviewed records of patients who presented to our plastic surgery service after sustaining acute GSWs involving the hand and wrist between 2016 and 2018. Results We identified 60 patients who sustained GSWs involving the hand and wrist; 17 (28%) were SI, and 43 (72%) were NSI. Within the SI group, 100% of patients were Caucasian, with an average age of 54 years. Within the NSI cohort, 77% of patients were Black, 19% were Caucasian, and 4% identified as other. While not statistically significant, we noted a substantial increase in patients requiring operative intervention in the SI cohort (65% SI vs 37% NSI, P = .08). There was a statistically significant increase in patients requiring more than 1 operation in SI patients (24% SI vs 5% NSI, P = .04). Patients who sustained SI injuries were also more likely to present with acute carpal tunnel syndrome requiring urgent surgical release and to develop wound infections (12% vs 0%, P = .08). Conclusions Self-inflicted GSWs involving the hand and wrist are associated with greater morbidity than their low-energy NSI counterparts. Individuals presenting with SI GSWs are more likely to be older, to require multiple operations, to develop infections, and to present with acute carpal tunnel syndrome requiring urgent surgical decompression.