bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the Niche ofRickettsia montanensis(Rickettsiales: Rickettsiaceae) Infection of the American Dog Tick (Acari: Ixodidae), Using Multiple Species Distribution Model Approaches
Authors: Lippi Catherine A , Gaff Holly D , White Alexis L , St. John Heidi K , Richards Allen L , Ryan Sadie J 
Published: December 2020

AbstractThe American dog tick, Dermacentor variabilis (Say) (Acari: Ixodidae), is a vector for several human disease-causing pathogens such as tularemia, Rocky Mountain spotted fever, and the understudied spotted fever group rickettsiae (SFGR) infection caused by Rickettsia montanensis. It is important for public health planning and intervention to understand the distribution of this tick and pathogen encounter risk. Risk is often described in terms of vector distribution, but greatest risk may be concentrated where more vectors are positive for a given pathogen. When assessing species distributions, the choice of modeling framework and spatial layers used to make predictions are important. We first updated the modeled distribution of D. variabilis and R. montanensis using maximum entropy (MaxEnt), refining bioclimatic data inputs, and including soil variables. We then compared geospatial predictions from five species distribution modeling frameworks. In contrast to previous work, we additionally assessed whether the R. montanensis positive D. variabilis distribution is nested within a larger overall D. variabilis distribution, representing a fitness cost hypothesis. We found that 1) adding soil layers improved the accuracy of the MaxEnt model; 2) the predicted ‘infected niche’ was smaller than the overall predicted niche across all models; and 3) each model predicted different sizes of suitable niche, at different levels of probability. Importantly, the models were not directly comparable in output style, which could create confusion in interpretation when developing planning tools. The random forest (RF) model had the best measured validity and fit, suggesting it may be most appropriate to these data.
Redescription of TwoPsathyromyiaSpecies (Diptera: Psychodidae), Including Description of the Female ofPsathyromyia pradobarrientosiUsing Molecular and Morphological Approaches
Authors: Costa Glaucilene da Silva , Rocha Douglas de Almeida , Júnior Antonio Marques Pereira , Ferreira Gabriel Eduardo Melim , Medeiros Jansen Fernandes , Gonçalves Rodrigo Gurgel , de Andrade Andrey José 
Published: December 2020

AbstractThe taxonomic identity of two species of sand flies, Psathyromyia pradobarrientosi (Le Pont, Matias, Martinez & Dujardin, 2004) and Psathyromyia runoides (Fairchild & Hertig, 1953) (Diptera, Psychodidae), was evaluated morphologically and molecularly based upon specimens collected in Brazilian states. The morphological component compared collected specimens with paratypes of Pa. runoides and Pa. pradobarrientosi and their descriptions. Phylogenetic analysis of coI sequences of Pa. pradobarrientosi showed a well-supported group distinct from Pa. runoides. Morphologically, Psathyromyia runoides and Pa. pradobarrientosi males are distinguished by characteristics of the aedeagal ducts and parameral sheath in the genitalia; females are distinguished by the number and shape of the teeth in the cibarium and by the shape of the spermathecae. Given the morphological similarity between the males and the absence of the description of the female of Pa. pradobarrientosi, it is possible that specimens previously identified as Pa. runoides in Brazil are in fact Pa. pradobarrientosi.
International Law in the US Legal System
Authors: Bradley Curtis A 
Published: December 2020

Abstract
International Law in the U.S. Legal System provides a wide-ranging overview of how international law intersects with the domestic legal system of the United States, and points out various unresolved issues and areas of controversy. Curtis Bradley explains the structure of the U.S. legal system and the various separation of powers and federalism considerations implicated by this structure, especially as these considerations relate to the conduct of foreign affairs. Against this backdrop, he covers all of the principal forms of international law: treaties, executive agreements, decisions and orders of international institutions, customary international law, and jus cogens norms. He also explores a number of issues that are implicated by the intersection of U.S. law and international law, such as treaty withdrawal, foreign sovereign immunity, international human rights litigation, war powers, extradition, and extraterritoriality. This book highlights recent decisions and events relating to the topic, including various actions taken during the Trump administration, while also taking into account relevant historical materials, including materials relating to the U.S. Constitutional Founding. Written by one of the most cited international law scholars in the United States, the book is a resource for lawyers, law students, legal scholars, and judges from around the world.
Crimes Against Humanity
Authors: Werle Gerhard , Jeßberger Florian 
Published: December 2020

Abstract
This chapter explains crimes against humanity. Crimes against humanity are mass crimes committed against a civilian population. Most serious is the killing of entire groups of people, which is also characteristic of genocide. Crimes against humanity target fundamental, recognised human rights, in particular life, health, freedom, and dignity. These violations of individual rights become international crimes when they are committed as part of a widespread or systematic attack on a civilian population. The chapter discusses the history and structure of the crime, as well as protected interests. It then presents the contextual element of this crime, which is an attack on a civilian population as defined in the ICC Statute. After this, individual acts committed as part of a widespread or systematic attack on a civilian population are next discussed. Lastly, this chapter explores the multiplicity of offenses within this category.
Treaties of Subjects of the Russian Federation
Authors: Butler William E 
Published: December 2020

Abstract
This chapter looks at how the "treaty" operates as a source of law, both domestic, international, and/or community, in ways that are not traditionally articulated in the classic expositions of sources of law. It considers how, historically, Russia's state-building or community-building enterprises have been bound up in the use of treaties to forge a sense of unity across its vast territory and among its myriad ethnic groups. The Soviet Union itself was a treaty-based federation, or confederation. Furthermore, the treaty is among the key instruments on which the Russian Federation rests, and underlying the treaty relations are principles of statehood, legal personality, autonomy, independence, dependence, and others which some view as constitutional questions and others as matters of international law. Movements in the direction of Eurasian integration presently underway (or not) reflect similar considerations. The treaty is the key vehicle.
Generally-Recognized Principles and Norms of International Law
Authors: Butler William E 
Published: December 2020

Abstract
This chapter studies the generally-recognized principles and norms of international law as an integral part of the Russian legal system. Most international lawyers would "rank" them higher than mere treaties because they are more fundamental, more universal, perhaps more venerable at least in origin. Indeed, in Article 15(4) of the 1993 Russian Constitution they are enumerated ahead of international treaties of the Russian Federation. However, they become important in Russian law and State practice precisely because they are provided for in Article 15(4) and thus are a comparatively recent addition to the repertoire of rules which Russian institutions, officials, and courts must apply, as a rule in priority over Russian normative legal acts. Chronologically, therefore, they appear in the Russian legal system long after treaties.
Conclusions
Authors: Butler William E 
Published: December 2020

Abstract
This concluding chapter reviews the major developments of the Russian treaty. It argues that the legal system of the Russian Federation contains two different kinds of law-international law and domestic law. Here, two distinctions are drawn with respect to international-legal norms: those having direct effect and not requiring domestic legislation in order to implement them, and those not having direct effect precisely because they do require implementing legislation. Although international law requires States acting in good faith to implement international legal obligations, in practice often that implementation never happens or occurs with great delay. Although not without controversy, the better position seems to be that generally-recognized principles and norms of international law enjoy priority over norms of Russian law which provide otherwise.
Interpreting the Energy Charter Treaty
Authors: Hobér Kaj 
Published: December 2020

Abstract
This chapter discusses the interpretation of the Energy Charter Treaty. The ECT is a multilateral treaty during the negotiation of which approximately fifty States participated, albeit to varying degrees. It goes without saying that in such a setting, there are many competing interests to take into account, often resulting in ambiguous treaty provisions. Indeed, almost every dispute based on the ECT involves issues of treaty interpretation. The law applicable to the interpretation of treaties is international law, unless the parties to the treaty in question have agreed otherwise. For all practical purposes, the most important international document when it comes to treaty interpretation is the 1969 Vienna Convention on the Law of Treaties. Article 2(1)(a) of the Vienna Convention defines ‘treaty’ as ‘an international agreement concluded between States in written form and governed by international law, whether embodied in a single instrument or in two or more related instruments and whatever its particular designation’. There is little doubt that the ECT is covered by this definition. Article 26(6) of the ECT provides that disputes under it are to be resolved on the basis of its provisions and ‘applicable rules and principles of international law’. The chapter then considers Articles 31—3 of the Vienna Convention, which deal with the interpretation of treaties.
Part V: Dispute Settlement
Authors: Hobér Kaj 
Published: December 2020

Abstract
This chapter highlights Part V of the Energy Charter Treaty, which deals with the settlement of disputes under the Treaty. Article 26 addresses investor-State disputes. It is central to the enforcement of the investment protection standards set out in Part III of the ECT. Article 26 offers an investor different options as to the method of settling disputes, including court proceedings and international arbitration. Meanwhile, Article 27 deals with disputes between Contracting Parties, i.e. inter-State disputes. It covers any dispute concerning the application or interpretation of the ECT, save for disputes concerning Articles 6 and 19 and for some Contracting Parties disputes concerning Article 10(1), last sentence of the Treaty. The dispute settlement method foreseen in Article 27 is ad hoc arbitration, provided that the disputing parties have been unable to settle the dispute through diplomatic channels. Article 28 exempts certain disputes from Article 27, namely disputes concerning the application and interpretation of Articles 5 and 29.
Part VI: Transitional Provisions
Authors: Hobér Kaj 
Published: December 2020

Abstract
This chapter discusses Part VI of the Energy Charter Treaty, which concerns transitional provisions. The present text of Article 29 of the ECT, entitled ‘Interim Provisions on Trade-Related Matters’, provides for a best endeavours tariff commitment for both Energy Materials and Products and Energy-Related Equipment. This is complemented by the possibility to move to a future, legally binding commitment for agreed items which are presently subject to the best endeavours commitment (paragraphs (6) and (7)). Article 30, entitled ‘Developments in International Trading Arrangements’, refers to the Trade Amendment in 1988 which entered into force in 2010. This article is therefore no longer relevant. Similarly, Article 31, entitled ‘Energy-Related Equipment’, is no longer applicable. Energy-Related Equipment was included in the provisions of the ECT by virtue of the Trade Amendment. Moreover, the transitional arrangements provided for in Article 32 were terminated on July 1, 2001, which means that the article is no longer applicable as well.
BIOM-07. EXPRESSION OF ANDROGEN RECEPTOR AND PROGRAMMED DEATH-LIGAND 1 IN BREAST-TO-BRAIN-METASTASES.
Authors: Qazi Maleeha , Jerzak Katarzyna , Nofech-Mozes Sharon 
Published: December 2020

Abstract

INTRODUCTION
Therapies targeting androgen receptors (AR) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated intracranial activity. In this study, we analyzed the expression of AR and PD-L1 in breast cancer brain metastases (BrM) to identify patients who may benefit from anti-androgenic or anti-PD-1/PD-L1 therapies.

METHODS
Consecutive BrM resected in our institution (July 1999-June 2013) that were signed out as breast origin were identified and included from the Anatomic Pathology departmental database. A tissue microarray of BrMs was studied by immunohistochemistry for AR, PD-L1, ER, PR and HER2 (SP107, SP142, SP1, IE2, 4B5; Ventana Medical Systems). HER2 gene amplification was determined by INFORM HER2 DNA and Chromosome 17 (Ventana Medical Systems). Immunohistochemistry was used as a surrogate to determine intrinsic subtypes.

RESULTS
Among 61 breast cancer BrM with available tissue blocks, AR was expressed in 38 (62%) cases and PD-L1 was expressed in 9 (15%) cases. Among BrMs of luminal A subtype (ER+PR+/-HER2-Ki67&lt; 16%; n=2), 50% expressed AR and none expressed PD-L1. Within the luminal B subtype (ER+/PR+/-), all 15 HER2+ BrM expressed AR (100%), while only 1 expressed PD-L1 (7%). Among HER2- luminal B subtype BrMs (n=16), 50% and 12.5% of cases expressed AR and PD-L1, respectively. In BrM of HER2+ subtype (ER-/PR-; n=14), 71% expressed AR and 14% expressed PD-L1. The frequency of AR+ (30%) and PD-L1+ (30%) cases was equivalent in triple negative BrM (ER-/PR-/HER2-; n=14).

CONCLUSION
Almost two-thirds of breast cancer BrM expressed AR, while only 15% expressed PD-L1. HER2+ luminal B and HER2+ subtypes were most likely to be AR+. Meanwhile, PD-L1 expression was predominant in the triple negative subgroup. Our data suggests that certain subtypes of breast cancer BrM are more likely to be AR+ or PD-L1+; intracranial efficacy of AR-antagonists and immunotherapy warrants investigation for breast cancer BrM, particularly in biomarker-positive subtypes.
BIOM-26. MOLECULAR PREDICTORS OF RESPONSE TO SELINEXOR IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Walker Christopher , Shen Yao , Mau-Soerensen Morten , Wen Patrick , van den Bent Martin , Plotkin Scott , Walenkamp Annemiek , Green Adam , Califano Andrea , Chang Hua , Tamir Sharon , Henegar Leah , Shacham Sharon , Alvarez Mariano , Landesman Yosef , Lassman Andrew 
Published: December 2020

Abstract
The nuclear export protein exportin 1 (XPO1) is overexpressed in many cancers, including GBM. Selinexor is an inhibitor of XPO1 that crosses the blood-brain-barrier and targets cancer cells by sequestering tumor suppressor proteins and oncoprotein mRNAs in the nucleus, inducing cancer cell apoptosis. We previously reported encouraging results from a phase II trial of selinexor for molecularly unselected patients with recurrent GBM (ASCO 2019). Pre-treatment tumors from 57 patients were exome and RNA sequenced to explore molecular correlates of response, in a hypothesis generating, post-hoc, exploratory analysis. We compared overall survival (OS) and progression-free survival (PFS) between mutated and wild-type patients. Two mutated genes were associated with longer survival in selinexor treated patients: DOCK8 (n=7; PFS, P=0.013, hazard ratio [HR]=3.75 [1.32–10.62]; overall survival, P=0.009, HR=15.39 [2.00–118.34]) and PDX1 (n=5, PFS, P=0.014, HR=4.468 [1.361–14.670]). Other commonly mutated genes in glioma, including IDH1 (n=9) were observed but not associated with survival. RNAseq data were used to infer differential protein activities, which were input into a machine learning model that compared patients with selinexor sensitive disease (best response of partial or complete response, n=7) and resistant disease (best response of progressive disease, n=23). We found the inferred activities of three proteins emerged as the most associated with response and could be combined in a model to accurately predict benefit from selinexor treatment (area under the ROC curve from leave one out cross validation = 0.89 permutation test P&lt; 0.04). The three proteins were ZC3H12A (also called MCPIP-1), a negative regulator of inflammation; RAB43, a member of the RAS family that binds GTP and regulates vesicle trafficking, and SOCS3, a suppressor of cytokine signaling that can antagonize JAK/STAT signaling. Together these data identified mutations and proteins activities for identifying patients most likely to benefit from selinexor treatment. Further studies are required for validation. ClinicalTrials.gov:NCT01986348.
BIOM-27. PREDICTIVE EVALUATION OF QUANTITATIVE SPATIAL PROFILING OF THE TUMOR MICROENVIRONMENT BY MULTIPLEX IMMUNOFLUORESCENCE IN RECURRENT GLIOBLASTOMA TREATED WITH PD-1 INHIBITORS
Authors: Cieremans David , Kim Ju Young , Valencia Ariana , Santos Justin Mercado , Bordeaux Jennifer , Tran Thai , Vaupel Christine , Dakappagari Naveen , Tangri Shabnam , Iwamoto Fabio 
Published: December 2020

Abstract

BACKGROUND
PD-1 inhibitors have shown limited efficacy in glioblastoma (GBM) due to microenvironment immunosuppression and low tumor mutational burden. In GBM, PD-L1 expression is not a predictive marker for response to PD-1 or PD-L1 inhibitors. Multiplex immunostaining panel technology allows for detailed analyses of tumor microenvironment cells and their interaction.

METHODS
Pre-treatment tumor tissue was collected retrospectively from 27 patients in our neurooncology database at Columbia University Irving Medical Center with primary glioblastoma who were diagnosed within the past three years, had surgery here, and were either treated with SOC therapy (n= 8) or PD-1 inhibitors at recurrence (n= 19). Multiplex immunofluorescence was done for 1) CD11b/IDO1/HLADR/GFAP, 2) PD1/PD-L1/GFAP, and 3) CD4/CD8/CD25/FoxP3/Ki67/GFAP.

RESULTS
Multiplex immunofluorescence panels did not show any correlation with outcomes in patients treated with SOC therapy (non-immunotherapy). Among the 19 patients treated with PD-1 inhibitors, those with more HLA-DR positive cells had worse outcomes (p= 0.02). PD-L1 expression on tumor cells was not predictive of outcomes. There was a correlation trend between PD-1/PD-L1 interaction score (p= 0.08), which measures density of PD-1-positive cells in proximity to PD-L1-positive cells, and outcomes. PTEN loss was correlated with higher Ki67 expression in both tumor cells (p= 0.05) and non-tumors cells (p= 0.03); however, this relationship was not found when looking at Ki67 in CD4+ cells, CD8+ cells, or CD4+CD8+ cells combined. This assay allowed us to evaluate tumor- associated macrophages, myeloid-derived suppressor cells, CD8+ lymphocytes, and CD4+ T regulatory cells; however, none of these were significant predictive markers for outcome.

CONCLUSION
Quantitative spatial profiling by multiplex immunofluorescence is feasible in FFPE glioblastoma tissue. More refined and extensive quantitative and spatial microenvironment analyses may allow for the development of biomarkers for immunotherapy in GBM.
BIOM-30. DECREASED B CELL AND ALTERED CD4+ T CELL SUBSET RATIO PREDICT FAVORABLE RESPONSE TO RUXOLINITIB IN HIGH-GRADE GLIOMAS
Authors: Rauf Yasmeen , Jia Xuefei , Lathia Justin , Peereboom David , Ahluwalia Manmeet 
Published: December 2020

Abstract
Altered cellular growth and suppression of anti-tumor immune response collectively drive progression and therapeutic resistance of high-grade gliomas (HGGs), suggesting that successful treatments will likely target these key mechanisms. Janus-associated kinase (JAK)-STAT pathway comprises one such therapeutic node, as STAT3 signaling is upregulated in proliferating glioma cells and immunosuppressive cell types. We performed retrospective analysis on 13 HGG patients treated with the JAK1/2 inhibitor ruxolinitib in combination with radiation or radiation plus temozolomide in a Phase I setting (NCT03514069). Disease progression and treatment response was determined based on the Response Assessment in Neuro-Oncology (RANO) criteria. Peripheral blood mononuclear cells (PBMCs) cells were collected from patients prior to treatment, and 2- 4- and 6-week time points to characterize early immunological changes that are indicative of treatment response with flow cytometry. 6 patients responded favorably, define as progression-free survival &gt;6 months. Investigation of myeloid and lymphoid cell populations revealed no differences in dendritic cell, myeloid-derived suppressor cell and CD8+ T cell subset frequencies in blood. Similarly, expression of checkpoint inhibitors PD-1, TIGIT, CTLA-4 and TIM3 were not altered with ruxolinitib treatment. However, there was a ~2-fold reduction in the frequency of peripheral B cells in favorable responders at 4-week time point, whereas the levels remained stable in non-responders (p&lt;0.05). In addition, while 5 out of 7 non-responders had increased CD4+ T cells by 4-weeks, 5 out of 6 responders had stable or reduced CD4+ T cells. This effect was driven by reduction in immunosuppressive regulatory T cells (Tregs) as the relative ratio of immunostimulatory T helper 1 (Th1)-to-Treg ratio was 3-fold higher in responders compared to non-responders. These results support evaluation of B and CD4+ T cells in the peripheral blood as biomarkers to identify HGG patients likely to benefit from such approach.
BIOM-36. THE UNIQUE METABOLOMICS BASED BIOMARKERS OF RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA
Authors: Dastmalchi Farhad , Karachi Aida , Mehkri Yusuf , Khattri Ram , Merritt Matthew , Kubilis Paul , Mitchell Duane , Rahman Maryam 
Published: December 2020

Abstract

INTRODUCTION
The adaptive immune response requires robust T cell proliferation and activation. These T cell changes are dependent on metabolic program shifts that can be measured using metabolomic analysis. The objective of this project was to identify a metabolomics profile to serve as a biomarker of response to immunotherapy for the treatment of brain tumors.

METHODS
GL261-gp100 tumor-bearing mice were received anti-PD1 or bone marrow-derived dendritic cell (DC) vaccine that was generated ex vivo. Urine samples were collected for Nuclear Magnetic Resonance (NMR) analysis. A more in-depth Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) revealed global metabolic changes induced with immunotherapy.

RESULTS
The metabolic changes were most dramatic at 24 hours post DC vaccination and slowly returned to baseline at 7 days post DC vaccination. The main drivers of the differences included creatine, n-dimethyl glycine, alanine, lactate, glucose, glutamine, leucine, citrate and formate. Anti-PD1 therapy-related metabolic changes were largest around day 20 post therapy and the main drivers of the differences included dimethyl sulfone, succinate, lactate and isobutyrate.

CONCLUSION
Immunotherapy results in systemic metabolic changes that serve as a biomarker treatment effect. These findings have translational relevance in predicting patients who will develop an immune response to immunotherapy and ultimately have better outcomes with treatment.