scholarly journals 289 Cadonilimab, an anti-PD1/CTLA4 bi-specific antibody with Fc effector null backbone

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Zhaoliang Huang ◽  
Xinghua Pang ◽  
Tingting Zhong ◽  
Na Chen ◽  
Xinrong He ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Safety Profile ◽  
Tumor Tissue ◽  
Jurkat Cells ◽  
Human Macrophage ◽  
List Type ◽  
Efficacy And Safety ◽  
Link Type ◽  
Dependent Cell ◽  
Ldh Release

BackgroundTumor infiltrating lymphocytes co-express PD-1 and CTLA-4 at much higher levels compared to normal tissues and peripheral blood cells, thus anti-PD1/CTLA4 bi-specific antibody with a preferential tumor tissue enrichment over normal tissue would contribute to enhanced efficacy and safety. Currently available anti-PD1 and anti-CTLA4 antibodies used in combination therapy are of residual bindings to FcγRs, which mediate antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), leading to compromise on efficacy and safety. Moreover, activated macrophage in tumor microenvironment plays key role in mediating immune suppression by secreting proinflammatory cytokines, such as IL-6. Cadonilimab, also known as AK104, is an IgG1 scaffold Fc-engineered antibody, which is designed to eliminate binding to FcγRs and C1q, and subsequently minimize lymphocyte loss, and antibody dependent cytokine release from macrophage, which associate with irAEs and poor prognosis in immunotherapy.1MethodsPD-1 and CTLA4 antigen co-binding activity of Cadonilimab was determined by Fortebio and assay of co-culture Cadonilimab with Hoechst33342-labelled Jurkat cells expressing PD-1 and CHO-K1-CTLA4 cells. Binding kinetics of Cadonilimab to C1q, FcγRIa, FcγRIIa_H131, FcγRIIa_R131, FcγRIIIa_V158 and FcγRIIIa_F158 were measured by Fortebio. ADCC, ADCP and CDC activities were determined in cellular assays. IL-6 and IL-8 from macrophage were detected in a assay of human macrophage and CHO-K1-PD1-CTLA4 cells co-culture.ResultsCadonilimab binds to the antigens PD-1 and CTLA-4 simultaneously, and as shown in figure.1, Cadonilimab cross-links cells expressing CTLA-4 with those expressing PD-1 (figure 1). Cadonilimab exhibited no binding to FcγRIa, FcγRIIa_H131, FcγRIIIa_V158, FcγRIIIa_F158 or C1q (table 1), eliciting no apparent ADCC, ADCP or CDC (figure 2). Cadonilimab induced no remarkable IL-6 or IL-8 release by human macrophage compared with combination of nivolumab and ipilimumab (figure 3). Clinical trials of Cadonilimab as monotherapy, in combination with chemotherapy or tyrosine kinase inhibitor, such as Lenvatinib and Anlotinib, to treat metastatic cervical cancer (NCT04380805), gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (NCT04728321), non-small cell lung cancer (NCT04647344) and hepatocellular carcinoma (NCT04444167) are ongoing, and a promising efficacy and acceptable safety profile were observed.Abstract 289 Figure 1AK104 crosslinks cells expressing CTLA-4 and PD-1. AK104 can crosslink cells expressing CTLA-4 with cells expressing PD-1. CTLA-4-expressing CHO-K1 cells were plated into the plates. Then the mixture of AK104 or control antibodies with Hoechst 33342 labelled PD-1-expressing Jurkat cells were added into the plates and incubated for 20min. After the incubation, suspended Jurkat cells were removed, and the crosslinking between PD-1 and CTLA-4 expressing cells was analyzed microscopically.Abstract 289 Figure 2ADCC, CDC and ADCP activities of AK104. (A) Antibody-dependent cell-mediated cytotoxicity (ADCC) activities of AK104 (hG1), a version of Cadonilimab with wildtype IgG1 scaffold and Cadonilimab were determined by measuring lactase dehydrogenase (LDH) release from 293T-CTLA4-PD1 cells. (B) Complementary-dependent cell-mediated cytotoxicity (CDC) activities of AK104 (hG1) and Cadonilimab were determined by measuring LDH release from 293T-CTLA4-PD1 cells. (C) Antibody-dependent cellular phagocytosis (ADCP) activities of AK104 (hG1) and Cadonilimab were studied by examining phagocytosis of CHO-K1-PD1-CTLA4 cells by murine bone marrow derived macrophages. Data are expressed as mean±SEM of two independent experiments.Abstract 289 Figure 3IL-8 and IL-6 secretion induced by AK104. Effects of Fc engineering of cadonilimab on the release of inflammatory cytokines. (A) IL-8 and (B) IL-6 by HPMMs in the presence of IFN-γ. Data are expressed as mean ±SEM of two independent experiments.Abstract 289 Table 1Affinity of AK104 to FcγRs and C1q. Affinity of cadonilimab to FcγRIa, FcγRIIa_H131, FcγRIIa_R131, FcγRIIIa_V158, FcγRIIIa_F158 and C1q.ConclusionsCadonilimab, an IgG1 antibody with Fc-engineering, exhibits neither Fc effector functions including ADCC, ADCP, CDC, nor activating macrophage to secret IL-6 or IL-8. Possible tumor tissue preferential retention of Cadonilimab over conventional anti-PD-1 and anti-CTLA-4 antibodies noted above could potentially lead to better safety profile.ReferenceYang F, He Z, Duan H, Zhang D, Li J, Yang H, Dorsey JF, Zou W, Ali Nabavizadeh S, Bagley SJ, Abdullah K, Brem S, Zhang L, Xu X, Byrne KT, Vonderheide RH, Gong Y, Fan Y. Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40. Nat Commun 2021 June 8;12(1):3424.

scholarly journals Homeopathy for Covid-19 in Primary Care: A structured summary of a study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ubiratan Cardinalli Adler ◽  
Maristela Schiabel Adler ◽  
Livia Mitchiguian Hotta ◽  
Ana Elisa Madureira Padula ◽  
Amarilys de Toledo Cesar ◽  
...  
Keyword(s):  
Primary Care ◽  
Alternative Hypothesis ◽  
University Hospital ◽  
List Type ◽  
Study Medication ◽  
Link Type ◽  
Care Protocol ◽  
Full Protocol ◽  
Isolation Period

Abstract Objectives To investigate the effectiveness and safety of homeopathic medicine Natrum muriaticum (LM2) for mild cases of COVID-19 in Primary Health Care. Trial design A randomized, two-armed (1:1), parallel, placebo-controlled, double-blind, clinical trial is being performed to test the following hypotheses: H0: homeopathic medicines = placebo (null hypothesis) vs. H1: homeopathic medicines ≠ placebo (alternative hypothesis) for mild cases of COVID-19 in Primary Care. Participants Setting: Primary Care of São Carlos – São Paulo – Brazil. One hundred participants aged 18 years or older, with Influenza-like symptoms and a positive RT-PCR for SARS-CoV-2. Willingness to give informed consent and to comply with the study procedures is also required. Exclusion criterium: severe acute respiratory syndrome. Intervention and comparator Homeopathy: 1 globule of Natrum muriaticum LM2 diluted in 20 mL of alcohol 30% and dispensed in a 30 ml bottle. Placebo: 20 mL of alcohol 30% dispensed in a 30 ml bottle. Posology: one drop taken orally every 4 hours (6 doses/day) while there is fever, cough, tiredness, or pain (headache, sore throat, muscle aches, chest pain, etc.) followed by one drop every 6 hours (4 doses/day) until the fourteenth day of use. The bottle of study medication should be submitted to 10 vigorous shakes (succussions) before each dose. Posology may be changed by telemedicine, with no break in blinding. Study medication should be maintained during home isolation. According to the Primary Care protocol, the home isolation period lasts until the 10th day after the appearance of the first symptom, or up to 72 hours without symptoms. Main outcomes The primary endpoint will be time to recovery, defined as the number of days elapsed before all COVID-19 Influenza-like symptoms are recorded as mild or absent during home isolation period. Secondary measures are recovery time for each COVID-19 symptom; score of the scale created for the study (COVID-Simile Scale); medicines used during follow-up; number of days of follow-up; number of visits to emergency services; number of hospitalizations; other symptoms and Adverse Events during home isolation period. Randomisation The study Statistician generated a block randomization list, using a 1:1 ratio of the two groups (denoted as A and B) and a web-based tool (http://www.random.org/lists). Blinding (masking) The clinical investigators, the statistician, the Primary Care teams, the study collaborators, and the participants will remain blinded from the identity of the two treatment groups until the end of the study. Numbers to be randomised (sample size) One hundred participants are planned to be randomized (1:1) to placebo (50) or homeopathy (50). Trial Status Protocol version/date May 21, 2020. Recruitment is ongoing. First participant was recruited/included on June 29,2020. Due to recruitment adaptations to Primary Care changes, the authors anticipate the trial will finish recruiting on April 10, 2021. Trial registration COVID-Simile Study was registered at the University Hospital Medical Information Network (UMIN - https://www.umin.ac.jp/ctr/index.htm) on June 1st, 2020, and the trial start date was June 15, 2020. Unique ID: UMIN000040602. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

scholarly journals Efficacy and safety of early target-controlled plasma volume replacement with a balanced gelatine solution versus a balanced electrolyte solution in patients with severe sepsis/septic shock: study protocol, design, and rationale of a prospective, randomized, controlled, double-blind, multicentric, international clinical trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Gernot Marx ◽  
Kai Zacharowski ◽  
Carole Ichai ◽  
Karim Asehnoune ◽  
Vladimír Černý ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Septic Shock ◽  
Severe Sepsis ◽  
Plasma Volume ◽  
Volume Replacement ◽  
Efficacy And Safety ◽  
Volume Responsiveness ◽  
Double Blind ◽  
Link Type ◽  
Icu Discharge

Abstract Background Sepsis is associated with capillary leakage and vasodilatation and leads to hypotension and tissue hypoperfusion. Early plasma volume replacement is required to achieve haemodynamic stability (HDS) and maintain adequate tissue oxygenation. The right choice of fluids to be used for plasma volume replacement (colloid or crystalloid solutions) is still a matter of debate, and large trials investigating the use of colloid solutions containing gelatine are missing. This study aims to investigate the efficacy and safety of plasma volume replacement using either a combined gelatine-crystalloid regime (1:1 ratio) or a pure crystalloid regime. Methods This is a prospective, controlled, randomized, double-blind, international, multicentric phase IV study with two parallel groups that is planned to be conducted at European intensive care units (ICUs) in a population of patients with hypovolaemia in severe sepsis/septic shock. A total of 608 eligible patients will be randomly assigned to receive either a gelatine-crystalloid regime (Gelaspan® 4% and Sterofundin® ISO, B. Braun Melsungen AG, in a 1:1 ratio) or a pure crystalloid regime (Sterofundin® ISO) for plasma volume replacement. The primary outcome is defined as the time needed to achieve HDS. Plasma volume replacement will be target-controlled, i.e. fluids will only be administered to volume-responsive patients. Volume responsiveness will be assessed through passive leg raising or fluid challenges. The safety and efficacy of both regimens will be assessed daily for 28 days or until ICU discharge (whichever occurs first) as the secondary outcomes of this study. Follow-up visits/calls will be scheduled on day 28 and day 90. Discussion This study aims to generate evidence regarding which regimen—a gelatine-crystalloid regimen or a pure crystalloid regimen—is more effective in achieving HDS in critically ill patients with hypovolaemia. Study participants in both groups will benefit from the increased safety of target-controlled plasma volume replacement, which prevents fluid administration to already haemodynamically stable patients and reduces the risk of harmful fluid overload. Trial registration The European clinical trial database EudraCT 2015-000057-20 and the ClinicalTrials.gov Protocol Registration and Results System ClinicalTrials.gov NCT02715466. Registered on 17 March 2016.

184 Two types of anti-TIGIT antibodies with distinct binding epitope and functional activities

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A198-A198
Author(s):  
Tingting Zhong ◽  
Xinghua Pang ◽  
Zhaoliang Huang ◽  
Na Chen ◽  
Xiaoping Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Mixed Culture ◽  
Cell Activity ◽  
Cross Reactivity ◽  
Binding Activity ◽  
Jurkat Cells ◽  
List Type ◽  
Dependent Manner ◽  
Vitro Assay

BackgroundTIGIT is an inhibitory receptor mainly expressed on natural killer (NK) cells, CD8+ T cells, CD4+ T cells and Treg cells. TIGIT competes with CD226 for binding with CD155. In cancers, CD155 has been reported to up-regulate on tumor cells, and TIGIT was found to increase on TILs.1 Activation of TIGIT/CD155 pathway would mediate immunosuppression in tumor; while blockade of TIGIT promotes anti-tumor immune response.MethodsAK126 and AK113 are two humanized anti-human TIGIT monoclonal antibodies developed by Akesobio. Binding activity of AK126 and AK113 to human TIGIT, and competitive binding activity with CD155 and CD112, were performed by using ELISA, Fortebio, and FACS assays. Cross-reactivity with cynomolgus monkey TIGIT and epitope binning were also tested by ELISA assay. In-vitro assay to investigate the activity to promote IL-2 secretion was performed in mixed-culture of Jurkat-TIGIT cells and THP-1 cells.ResultsAK126 and AK113 could specifically bind to human TIGIT with comparative affinity and effectively blocked the binding of human CD155 and CD112 to human TIGIT. X-ray crystal structure of TIGIT and PVR revealed the C’-C’’ loop and FG loop regions of TIGIT are the main PVR interaction regions.2 The only amino acid residue differences in these regions between human and monkey TIGIT are 70C and 73D. AK126 binds to both human and monkey TIGIT, AK113 binds only to monkey TIGIT. This suggests that these residues are required for AK113 binding to human TIGIT, but not required for AK126. Interestingly, results from cell-based assays indicated that AK126 and AK113 showed significantly different activity to induce IL-2 secretion in mixed-culture of Jurkat-TIGIT cells and THP-1 cells (figure 1A and B), in which AK126 had a comparable capacity of activity to 22G2, a leading TIGIT mAb developed by another company, to induce IL-2 secretion, while, AK113 showed a significantly higher capacity than 22G2 and AK126.Abstract 184 Figure 1Anti-TIGIT Antibodies Rescues IL-2 Production in Vitro T-Cell Activity Assay in a dose dependent manner. Jurkat-TIGIT cells (Jurkat cells engineered to over-express human TIGIT) were co-cultured with THP-1 cells, and stimulated with plate-bound anti-CD3 mAb in the presence of TIGIT ligand CD155 (A) or CD112 (B) with anti-TIGIT antibodies. After incubated for 48h at 37° C and 5.0% CO2, IL-2 levels were assessed in culture supernatants by ELISA. Data shown as mean with SEM for n = 2.ConclusionsWe discovered two distinct types of TIGIT antibodies with differences in both epitope binding and functional activity. The mechanism of action and clinical significance of these antibodies require further investigation.ReferencesSolomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018;67:1659–1667.Stengel KF, Harden-Bowles K, Yu X, et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci USA 2012;109:5399–5404.

scholarly journals 4CPS-294 Efficacy and safety profile of trifluridine–tipiracil and regorafenib in the treatment of metastatic colorectal cancer

2021 ◽  
Author(s):  
L Cantarelli ◽  
JA Morales Barrios ◽  
F Gutierrez Nicolas ◽  
S Garcia Gil ◽  
B Del Rosario Garcia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Safety Profile ◽  
Efficacy And Safety

scholarly journals Inter-professional agreement and collaboration between extended scope physiotherapists and orthopaedic surgeons in an orthopaedic outpatient shoulder clinic – a mixed methods study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Merete Nørgaard Madsen ◽  
Maria Lange Kirkegaard ◽  
Thomas Martin Klebe ◽  
Charlotte Lorenzen Linnebjerg ◽  
Søren Martin Riis Villumsen ◽  
...  
Keyword(s):  
Treatment Plan ◽  
Random Order ◽  
Primary Diagnosis ◽  
Diagnosis And Treatment ◽  
List Type ◽  
Professional Collaboration ◽  
Relational Coordination ◽  
Orthopaedic Surgeons ◽  
Link Type ◽  
Shoulder Disorders

Abstract Background Extended scope physiotherapists (ESP) are increasingly supplementing orthopaedic surgeons (OS) in diagnosing patients with musculoskeletal disorders. Studies have reported satisfactory diagnostic and treatment agreement between ESPs and OSs, but methodological study quality is generally low, and only few studies have evaluated inter-professional collaboration. Our aims were: 1) to evaluate agreement on diagnosis and treatment plan between ESPs and OSs examining patients with shoulder disorders, 2) to explore and evaluate their inter-professional collaboration. Methods In an orthopaedic outpatient shoulder clinic, 69 patients were examined independently twice on the same day by an ESP and an OS in random order. Primary and secondary diagnoses (nine categories) and treatment plan (five categories, combinations allowed) were registered by each professional and compared. Percentage of agreement and kappa-values were calculated. Two semi-structured focus-group interviews were performed with ESPs and OSs, respectively. Interviews were based on the theoretical concept of Relational Coordination, encompassing seven dimensions of communication and relationship among professionals. A thematic analysis was conducted. Results Agreement on primary diagnosis was 62% (95% CI: [50; 73]). ESPs and OSs agreed on the combination of diagnoses in 79% (95% CI: [70; 89]) of the cases. Partial diagnostic agreement (one professional’s primary diagnosis was also registered as either primary or secondary diagnosis by the other) was 96% (95% CI: [91; 100]). Across treatment categories, agreement varied between 68% (95% CI: [57; 79]) and 100%. In 43% (95% CI: [31; 54]) of the cases, ESP and OS had full concordance between treatment categories chosen, while they agreed on at least one recommendation in 96% (95% CI: [91; 100]). Positive statements of all dimensions of relational coordination were found. Three themes especially important in the inter-professional collaboration emerged: Close communication, equal and respectful relationship and professional skills. Conclusions In the majority of cases, the ESP and OS registered the same or partly the same diagnosis and treatment plan. Indications of a high relational coordination implying a good inter-professional collaboration were found. Our results support that ESPs and OSs can share the task of examining selected patients with shoulder disorders in an orthopaedic clinic. Trial registration ClinicalTrials.gov Identifier: NCT03343951. Registered 10 November 2017

347 Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A372-A373
Author(s):  
Ira Winer ◽  
Lucy Gilbert ◽  
Ulka Vaishampayan ◽  
Seth Rosen ◽  
Christopher Hoimes ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Marker ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Comprehensive Cancer Center ◽  
List Type ◽  
Link Type ◽  
Heavily Pretreated

BackgroundALKS 4230 is a novel engineered cytokine that selectively targets the intermediate-affinity interleukin-2 receptor complex to activate CD8+ T cells and natural killer cells.1 The ARTISTRY-1 trial (NCT02799095) has shown encouraging efficacy and acceptable tolerability of ALKS 4230 among patients with advanced solid tumors.2 We report a detailed analysis of ovarian cancer (OC) patients who received combination therapy in ARTISTRY-1.MethodsARTISTRY-1 is an ongoing multicohort phase 1/2 trial exploring intravenous ALKS 4230 as monotherapy and combined with pembrolizumab. OC patients were enrolled into a cohort with mixed anti PD 1/L1 unapproved tumor types who had progressed on prior chemotherapy. OC patients received ALKS 4230 (3 µg/kg) on days 1–5 and pembrolizumab (200 mg) on day 1 of a 21 day cycle. Outcomes presented include antitumor activity (RECIST v1.1) and safety as of 7/24/2020. To evaluate changes in tumor microenvironment (TME), baseline and on-treatment biopsies were collected.ResultsFourteen heavily pretreated patients with OC were enrolled. Patients received a median of 5 (range, 2 11) prior regimens and all were previously treated with platinum based therapy. Among 13 evaluable patients with ≥1 assessment, 9 experienced disease control and 4 experienced disease progression; median treatment duration was approximately 7 weeks. Three patients experienced an objective response, including 1 complete response, 1 partial response (PR), and 1 unconfirmed PR; all were platinum resistant and negative for BRCA mutations. Five patients experienced tumor burden reductions (table 1). Treatment-related adverse events at the doses tested have generally been transient and manageable, with the majority being grade 1 and 2 in severity. Overall, based on preliminary data, the combination with ALKS 4230 did not demonstrate any additive toxicity to that already established with pembrolizumab alone. Additional safety and efficacy data are being collected in ongoing cohorts. In the monotherapy dose escalation portion of the study, ALKS 4230 alone increased markers of lymphocyte infiltration in 1 paired melanoma biopsy (1 of 1; on treatment at cycle 2); CD8+ T cell density and PD-L1 tumor proportion score increased 5.2- and 11 fold, respectively, supporting evidence that ALKS 4230 has immunostimulatory impact on the TME and providing rationale for combining ALKS 4230 with pembrolizumab (figure 1).Abstract 347 Table 1Summary of response observations among patients with ovarian cancerAbstract 347 Figure 1Increased markers of lymphocyte tumor infiltrationAn increase in CD3+CD8+ T cells (A, red = CD3; blue = CD8; purple = CD3+CD8+; teal = tumor marker), GranzymeB (B, red = CD8; green = granzymeB; yellow = granzymeB+CD8+; teal = tumor marker), and PD-L1 (C, red = PD-L1; blue = tumor marker) in the tumor microenvironment of a single patient was observed after the patient received monotherapy ALKS 4230ConclusionsThe combination of ALKS 4230, an investigational agent, and pembrolizumab demonstrates an acceptable safety profile and provides some evidence of tumor shrinkage and disease stabilization in some patients with heavily pretreated OC. This regimen could represent a new therapeutic option for these patients.AcknowledgementsThe authors would like to thank all of the patients who are participating in this trial and their families. The trial is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Parexel and funded by Alkermes, Inc.Trial RegistrationClinicalTrials. gov NCT02799095Ethics ApprovalThis trial was approved by Ethics and Institutional Review Boards (IRBs) at all trial sites; IRB reference numbers 16–229 (Dana-Farber Cancer Institute), MOD00003422/PH285316 (Roswell Park Comprehensive Cancer Center), 20160175 (Western IRB), i15-01394_MOD23 (New York University School of Medicine), TRIAL20190090 (Cleveland Clinic), and 0000097 (ADVARRA).ReferencesLopes JE, Fisher JL, Flick HL, Wang C, Sun L, Ernstoff MS, et al. ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy. J Immunother Cancer 2020;8:e000673. doi: 10.1136/jitc-2020-000673.Vaishampayan UN, Muzaffar J, Velcheti V, Winer I, Hoimes CJ, Rosen SD, et al. ALKS 4230 monotherapy and in combination with pembrolizumab (pembro) in patients (pts) with refractory solid tumors (ARTISTRY-1). Oral presentation at: European Society for Medical Oncology Annual Meeting; September 2020; virtual.

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