Journal articles on the topic 'A. K. Gopalan'

Abstract Recent studies exploring the impact of methylation in tumor evolution suggest that while the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Since changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and jointly identifying lineage-informative CpG sites which harbor changes in methylation status that are retained along the lineage. We apply Sgootr on the single-cell bisulfite-treated whole genome sequencing data of multiregionally-sampled tumor cells from 9 metastatic colorectal cancer patients made available by Bian et al., as well as multiregionally-sampled single-cell reduced-representation bisulfite sequencing data from a glioblastoma patient made available by Chaligne et al. We demonstrate that the tumor lineages constructed reveal a simple model underlying colorectal tumor progression and metastatic seeding. A comparison of Sgootr against alternative approaches shows that Sgootr can construct lineage trees with fewer migration events and more in concordance with the sequential-progression model of tumor evolution, in time a fraction of that used in prior studies. Interestingly, lineage-informative CpG sites identified by Sgootr are in inter-CpG island (CGI) regions, as opposed to CGI's, which have been the main regions of interest in genomic methylation-related analyses. Sgootr is implemented as a Snakemake workflow, available at https://github.com/liuy0421/Sgootr. Citation Format: Xuan C. Li, Yuelin Liu, Farid Rashidi Mehrabadi, Alejandro A. Schäffer, Drew Pratt, David R. Crawford, Salem Malikić, Erin K. Molloy, Vishaka Gopalan, Stephen M. Mount, Eytan Ruppin, Kenneth Aldape, S. Cenk Sahinalp. Single-cell methylation sequencing data reveals succinct metastatic migration histories and tumor progression models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 127.

Abstract Protein folding complexes are a vital link between the expression of tumor-promoting oncogenes and oncogenic cancer behavior known as the hallmarks of cancer. Of these, the eukaryotic type II chaperonin, Chaperonin-Containing TCP-1 (CCT or TRiC) folds many of the oncoproteins (e.g., KRAS, MYC, CDKs, STAT3, etc.) that drive cancer growth and invasion. CCT is a complex machine composed of eight subunits, each encoded by a unique gene (cct1-8), which folds proteins in an ATP-dependent fashion within an inner chamber. Previous work in breast cancer revealed that the CCT2 subunit was highly expressed in breast tumor tissues and correlated with advanced breast cancer stage, metastasis, and decreased patient survival. To determine the pattern of CCT2 expression across multiple cancers in comparison to normal tissues, we interrogated the UCSC Xena database to compare cohorts, GTEx (normal tissues), TCGA (adult cancerous and normal tissues), and TARGET (pediatric cancerous and normal tissues). Tumor specimens from adult TCGA expressed significantly higher levels of CCT2 than GTEx, and pediatric TARGET samples had significantly higher expression levels of CCT2 than TCGA and normal samples. Histological detection of CCT2 in multiple cancer tissues was increased (e.g., pediatric cancers and sarcomas being among the highest) compared to cancer-adjacent tissues or normal tissues and supported the bioinformatics data. Manipulating CCT2 levels in individual breast, neuroblastoma, and prostate cancer cells revealed the strategic importance of this chaperonin subunit in supporting the metastatic cancer phenotype. Exogenous expression of CCT2 promoted uncontrolled and anchorage-independent growth and migration of cancer cells, which was reversed upon depletion of the subunit, causing cancer cell death. Moreover, conditioned media from cancer cells exogenously expressing CCT2 also drove the migration and growth of cancer cells. Exosomes isolated from this media contained high levels of CCT2 mRNA, further demonstrating the metastasis-promoting potential of this chaperonin subunit. The feasibility of using CCT2 as a biomarker to detect cancer progression was confirmed using antibodies to detect CCT2 in the identification of circulating tumor cells using the CellSearch System. These results provide validation to further develop the use of CCT2 as a diagnostic marker for cancer progression and metastasis and as a promising therapeutic target for new drug development. Citation Format: Annette R. Khaled, James Velazquez, Lam Truong, Colten Frank, Carolyn Dang, Amanda Cox, Heba Ghozlan, Eunkyung Lee, Amr S. Khaled, Priya K. Gopalan. Protein folding chaperonin as biological indicator for cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2463.

This study examines the poverty and food security analysis of fishermen households in a selected area of Gopalganj Sadar Upazila in Gopalganj District in Bangladesh. A sample size of 60 households was selected purposively from four villages. Data was collected through field survey by using pre-designed and pre-tested questionnaire. Calorie intake levels were calculated and statistical comparisons were done. Multiple regression analysis was carried out to determine the factor influencing calorie intake in individual levels. Food consumption scores were used to determine calorie intake levels. The major findings of the study were that income, education, cultivable area and rented area had positive impact on calorie intake but age of the respondents and family size had negative impact on calorie intake. About 68.33% of the respondents belonged to hard core poor whose average calorie intake was 1692.32 k. calories and 25% of the respondents had an average calorie intake 1890.93 k. calories and they belonged to absolute poor. The rest 6.67 % of the respondents took above 2122 kilo calories and average calorie intake was 2193.50 k. calories. There was 20% households having poor food consumption and 42% having borderline food consumption. Only 6.67% fishermen households have acceptable low food consumption and 3.33% have acceptable high food consumption. DOI: http://dx.doi.org/10.3329/jbau.v11i2.19928 J. Bangladesh Agril. Univ. 11(2): 293-299, 2013

The intellectual anthropology that studies human beings examines human beings and human society at three levels: biological anthropology, social anthropology, and cultural anthropology. It is ethnography to trace the culture of a particular group of people in Tamilnadu, where different cultures and customs prevail. In that respect, the purpose of this study is to find ethnographic data in the novel Gopalla Gramam by the author K. Rajanarayanan, based on the biographies of the people of the Karisal area. In this study, the concepts like "what is ethnography? What are the cultural researchers' references to data to identify them? How are the data on food, artefacts, beliefs, customs, agriculture, plants, animals, birds, land, water, vernaculars, stories, songs, etc., recorded in the Gopalla Gramam novel to define the ethnography of the Karisal soil" have been identified. How they represent the uniqueness and identity of the black soil is also under scrutiny.

Dielectric relaxation of the binary mixture of tetramethylurea andN, N-dimethylacetamide has been studied at fixed frequency and temperature (9.88 GHz & 298 K respectively) in benzene solution. Different dielectric parameters like the dielectric constant (ε') and the dielectric loss (ε") at microwave frequency, static dielectric constant (ε0) and dielectric constant (ε∞) at optical frequency were determined. The values of relaxation time (τ(1), τ(2), τ(0)& τGK) have been calculated using higasi’s single frequency method and Gopala Krishna’s method. Using Eyring’s rate theory, the activation energies for the process of dielectric relaxation and viscous flow were calculated and compared. The study of dielectric properties of the binary mixture reveals the existence of the solute-solute type of molecular associations.

Overcoming malnutrition through biofortification breeding in rice is aimed to assist nutritional food security in Bangladesh. So to select parents for nutritional improvement, estimation and exploitation of mineral nutrients reserves of rice grain and their variability assessment in different genotypes is essential. Eighty-five (85) T. aman rice genotypes collected from different coastal regions of Bangladesh were evaluated at the Advanced Plant Breeding laboratory, GPB of BSMRAU to estimate the grain nutrients content and to elucidate their genetic variability among the genotypes. Considerable significant variation (0.1% level of probability) was noted among the genotypes for studied different grain nutrient contents and yield per hill. The mean values of N, P, K, Ca, Mg, Na, Zn, Fe, Cu, Mn and grain yield/ hill were 10788.24 mg/kg, 804.85 mg/kg, 3798.58 mg/kg, 13795.29 mg/kg, 2778.87 mg/kg, 3771.17 mg/kg, 7.25 mg/kg, 5.01 mg/kg, 1.05 mg/kg, 1.90 mg/kg and 433.29 g, respectively. Box and whisker plots analysis were done to represent data graphically for better understanding. Histogram was used to present the frequency distribution of genotypes for N, P, K, Ca, Mg, Na, Zn, Fe, Cu, Mg and Grain yield/hill content in 85 diverged rice genotypes All the traits had equality in genotypic and phenotypic variances with high heritability and high genetic advance which indicated preponderance of additive gene effects for these traits. The genotype R080 (Chinigura) contained the highest content of grain P, Fe and Cu. The R030 (Mota Dhan), R040 (Dudh Kalam) and R019 (Chikon Dhan) were noted for the highest Ca, Mg and Na content, respectively. The maximum N and Zn content were observed in R029 (Dudh Kolom) and R075 (Gopal Bogh), respectively. R083 (Lal Dhan) was marked for the highest grain yield/ hill and K content. Genetic variability parameters, heat map analysis and neighbor joining clustering methods indicated these genotypes including R079 can be considered for biofortification program and used as parents for the improvement of those grain nutrients in rice breeding.

Fifty-seven rice germplasm collected from BRRI Genebank were screened against sheath blight (ShB) by artificial inoculation in field and laboratory conditions in T. Aman 2012. Significant differences on relation to lesion height (RLH) among the germplasm were observed, where the highest (83%) was recorded in susceptible check, BR11 and the lowest (8.33%) was in Orgoja. Severity score of ShB was recorded maximum (9) in Dudhsail, Basi, Chaula mari, Holdemota, Calendamota, Semmua, Kotijira, Halisail, Horakani, Kalisura, Ashfuli, Huglapata and BR11 as highly susceptible to ShB, whereas it was minimum (1) in Orgoja. Gopal ghosh was observed as moderately tolerant with 27.33% RLH and severity score 3, while Kala binni, Khazur chari, Binni, Kalagora, Patjait and Dorkumur found moderately tolerant with severity score 5. In detached sheath inoculation method in test tube, most of the germplasms found highly susceptible, except Orgoja as resistant and Gopal ghosh as moderately tolerant. However, Orgoja showed resistance in both field inoculation and detached sheath inoculation methods. But, Dorkumur was found moderately tolerant in field and highly susceptible in detached sheath inoculation in laboratory. The experiment of Integrated Disease Management (IDM) packages was conducted in the farmer’s field with BR11 at Fulpur, Mymensingh during T. Aman 2013. The IDM practices of rice ShB resulted profound effect. Relative lesion height, percent disease index, tiller infection and hill infection were maximum (68%, 69%, 86% and 79% respectively) in T6 (control) and minimum in T1 [FDR (removal of floating debris) + 30 July transplanting + Potash (K) fertilizer (202 g decimal-1) + Top dressing of urea (247 kg ha-1) in four equal splits at 15 days interval + single spray of fungicides of Azoxystrobin 10% (0.17 kg ha-1) + Tebuconazole 90% (500 ml ha-1)]. Moreover, the highest number of panicles per m2, filled grains per panicle and grains yield were recorded in T1 (160, 150 and 6.25 t ha-1 respectively) and the minimum in T6 (227, 120 and 3.6 t ha-1 respectively). Therefore, the best IDM package was T1 for its effective control of ShB disease as well as yield maximization of rice. Finally, Orgoja could be used in resistance breeding for varietal improvement and the IDM package of T1 need to be recommended to prescribe in the farmer’s field after simulation in different AEZs and seasons with different varieties of Bangladesh. Bangladesh Rice j. 2018, 22(2): 1-12

ABSTRACT Aim This study was conducted to evaluate the antimicrobial activity of 5.25% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX) and BioPure MTAD when used as a final rinse against Enterococcus faecalis. Materials and methods Sixty single-rooted premolars were biomechanically prepared, inoculated with E. faecalis and divided into various groups. These were then irrigated with the test irrigants and tested microbiologically for growth of E. faecalis immediately after irrigation and after 48 hours. Results Statistical analysis showed that there was a significant difference between the antibacterial activities of BioPure MTAD, 2% CHX and 5.25% NaOCl at 5 minutes; however, the antibacterial activities of the three irrigants were comparable after 2 days of irrigation Conclusion The present study concludes that BioPure MTAD is as effective against E. faecalis as 5.25% NaOCl and more effective than 2% CHX. Clinical significance E. faecalis is one of the most resistant intracanal species and a possible cause of root canal failure. Many authors have stressed the importance of using antimicrobial irrigants during chemomechanical preparation to ensure complete disinfection. Therefore, various irrigating solutions have been used during and immediately after root canal preparation to remove debris and necrotic pulp tissue and to eliminate microorganisms that cannot be reached by mechanical instrumentation. How to cite this article Agrawal V, Rao MSR, Dhingra K, Gopal VR, Mohapatra A, Mohapatra A. An in vitro comparison of Antimicrobial Efficacy of Three Root Canal Irrigants—BioPure MTAD, 2% Chlorhexidine Gluconate and 5.25% Sodium Hypochlorite as a Final Rinse against E. faecalis. J Contemp Dent Pract 2013;14(5):842-847.

New developments and publications on in alkali metal solid-state batteries appear regularly, with the number of publications now numbering in the hundreds to low thousands, but the search and analysis of the data contained in these publications is still largely done by manually reading through each article. Such challenges are also present in other fields, such as perovskite solar cells, for which successful efforts to create a database have been pursued. Review articles can provide valuable summaries and insights on groupings of these publications, but the rapid rate of development and the “static” nature of a review paper limits their usefulness. As such, a structured database is desirable to facilitate the search of public reports for specific cell conditions or cell performance, and to provide data in electronic and internationally accessible format to allow for analysis with a range of statistical and machine learning tools. However, defining an ontology that can efficiently capture the large range of materials, cell designs, processing conditions, test conditions, and results is required for a broadly useful database. Here we discuss our efforts in developing an ontology for solid-state battery cells, and preliminary results on a database we are constructing based on that ontology. Key areas for the ontology include component material identities, material properties, component properties (e.g., active material loading, mass fractions, thicknesses), processing conditions for materials and the cell itself (e.g., ball milling time, sintering time), and both performance (e.g., rate capability) and degradation (e.g., cycle life). We welcome feedback from the community interested in or engaged in similar and growing efforts to more systematically define and make available the large volumes of battery data currently being reported. (1) Ward, L.; Babinec, S.; Dufek, E. J.; Howey, D. A.; Viswanathan, V.; Aykol, M.; Beck, D. A. C.; Blaiszik, B.; Chen, B. R.; Crabtree, G.; Clark, S.; De Angelis, V.; Dechent, P.; Dubarry, M.; Eggleton, E. E.; Finegan, D. P.; Foster, I.; Gopal, C. B.; Herring, P. K.; Hu, V. W.; Paulson, N. H.; Preger, Y.; Uwe-Sauer, D.; Smith, K.; Snyder, S. W.; Sripad, S.; Tanim, T. R.; Teo, L. Principles of the Battery Data Genome. Joule 2022, 6 (10), 2253–2271. https://doi.org/10.1016/J.JOULE.2022.08.008. (2) Jacobsson, T. J.; Hultqvist, A.; García-Fernández, A.; Anand, A.; Al-Ashouri, A.; Hagfeldt, A.; Crovetto, A.; Abate, A.; Ricciardulli, A. G.; Vijayan, A.; Kulkarni, A.; Anderson, A. Y.; Darwich, B. P.; Yang, B.; Coles, B. L.; Perini, C. A. R.; Rehermann, C.; Ramirez, D.; Fairen-Jimenez, D.; Di Girolamo, D.; Jia, D.; Avila, E.; Juarez-Perez, E. J.; Baumann, F.; Mathies, F.; González, G. S. A.; Boschloo, G.; Nasti, G.; Paramasivam, G.; Martínez-Denegri, G.; Näsström, H.; Michaels, H.; Köbler, H.; Wu, H.; Benesperi, I.; Dar, M. I.; Bayrak Pehlivan, I.; Gould, I. E.; Vagott, J. N.; Dagar, J.; Kettle, J.; Yang, J.; Li, J.; Smith, J. A.; Pascual, J.; Jerónimo-Rendón, J. J.; Montoya, J. F.; Correa-Baena, J. P.; Qiu, J.; Wang, J.; Sveinbjörnsson, K.; Hirselandt, K.; Dey, K.; Frohna, K.; Mathies, L.; Castriotta, L. A.; Aldamasy, M. H.; Vasquez-Montoya, M.; Ruiz-Preciado, M. A.; Flatken, M. A.; Khenkin, M. V.; Grischek, M.; Kedia, M.; Saliba, M.; Anaya, M.; Veldhoen, M.; Arora, N.; Shargaieva, O.; Maus, O.; Game, O. S.; Yudilevich, O.; Fassl, P.; Zhou, Q.; Betancur, R.; Munir, R.; Patidar, R.; Stranks, S. D.; Alam, S.; Kar, S.; Unold, T.; Abzieher, T.; Edvinsson, T.; David, T. W.; Paetzold, U. W.; Zia, W.; Fu, W.; Zuo, W.; Schröder, V. R. F.; Tress, W.; Zhang, X.; Chiang, Y. H.; Iqbal, Z.; Xie, Z.; Unger, E. An Open-Access Database and Analysis Tool for Perovskite Solar Cells Based on the FAIR Data Principles. Nature Energy 2021 7:1 2021, 7 (1), 107–115. https://doi.org/10.1038/s41560-021-00941-3.

Citrus mosaic disease, a potential threat to citrus production throughout India, is currently an important disease in the southern and northeastern states (2). The reported incidence of the disease ranges from 10 to 77% (K. Gopal, G. S. Aparna, M. Sreenivasuluk, K. V. Subbaiah, and A. R. K. Rao, unpublished data). This yellow mosaic disease of citrus is caused by Citrus yellow mosaic badna virus (CMBV), formerly citrus yellow mosaic disease, (CYMD) (1). Host range studies were done to find herbaceous noncitrus host plant species for virus maintenance. The following are the noncitrus plants tested in this study: Arachis hypogaea, Chenopodium amaranticolor, Chenopodium quinoa, Vigna mungo, Macrotyloma uniflorum, Cicer arietinum, Helianthus annuus, Cajanus cajan, V. sinensis, Cyamopsis tetragonoloba, V. radiata, Pisum sativum, Phaseolus vulgaris, Trichosanthes anguina, Nicotiana tabacum (Harrison special), Dolichos lablab, Petunia × hybrida, Gomphrena globosa, Cucumis melo, Cucumis pepo, Glycine max, Sorghum bicolor, Zea mays, and Canna indica. Young leaves with mosaic symptoms were collected from Citrus sinensis Osbeck, Citrus aurantiifolia Osbeck, and Citrus × limonia Osbeck plants, which are being maintained in an insect-proof glasshouse. The leaves were cut into small pieces, transferred to a chilled mortar, and macerated using 0.01 M phosphate buffer, pH 7.0, containing 0.2% (v/v) of 2-mercapto-ethanol at a tissue/buffer ratio of 1 g/9 ml (wt/vol). The extract was filtered and used for inoculation. The above-mentioned noncitrus plants were uniformly dusted with 600-mesh Carborundum and inoculated with sap extract from the citrus species. The plants were kept in an insect-proof glasshouse and observed for 6 weeks for symptom development. Only three hosts, Canna indica, sorghum, and maize produced visible symptoms. Symptoms were observed 14 days postinoculation on C. indica as chlorotic spots, which later developed into a mosaic pattern. Developing young leaves showed severe mosaic with vein banding symptoms. In sorghum and maize, chlorotic streaks were observed on young leaves after 10 days, which developed into dark green streaks in the leaf lamina. All the inoculated hosts were checked using virus double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) and dot blot ELISA using CMBV polyclonal antiserum (Department of Virology, S.V. University, Tirupati, India). In both tests, only the C. indica, sorghum, and maize samples reacted positively. In dot blot ELISA, as little as 100 ng of virus could be detected in C. indica, sorghum, and maize. Virus from all three citrus sources produced the same symptoms on C. indica, sorghum, and maize. To our knowledge, this is the first report of herbaceous hosts of CMBV, which should prove useful as propagation and index hosts for CMBV. References: (1) Y. S. Ahlawat et al. Plant Dis. 80:590, 1996. (2) G. S. Reddy et al. Page 130 in: 3rd Int. Symp. Subtrop. Hortic. Bangalore, 1972.

Abstract Background: Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related mortality in the United States. Furthermore, advanced HCC has a very poor prognosis, with a median survival time of only about ten months. Effective new targeted therapies are urgently needed for the treatment of HCC. Proline, glutamic acid-, and leucine-rich protein 1 (PELP1) is a protooncogene. PELP1 signaling has been implicated in the development of several cancers, however, its role in the progression of HCC remains unclear. The goal of this project is to investigate the significance and therapeutic potential of targeting PELP1 in HCC. Methods: In this investigation, we have used six HCC cell lines (HUH7, HEP3B, SNU398, SNU475, SNU423, and SNU449). Using immunohistochemistry (IHC), the expression of PELP1 in HCC tissue microarrays was examined. PELP1shRNA lentiviral particles were used to create PELP1 knockdown (KD) cells. Using well-established in vitro tests for cell proliferation, colony formation, and apoptosis, the effects of PELP1 KD or PELP1 inhibitor (SMIP34) were investigated. RNA-seq, RT-qPCR, Western blotting, IHC, reporter gene assays, and signaling pathway analysis were used in mechanistic investigations. Preclinical evaluations were conducted using mice xenograft models. Results: TNM plot analysis showed that HCC samples had increased PELP1 expression relative to normal tissue. Immunohistochemistry analysis of tissue microarray confirmed that HCC specimens overexpressed PELP1 in comparison to normal specimens. PELP1 knockdown with shRNA dramatically decreased HCC cell invasion, clonogenicity, and proliferation. Similarly, PELP1 inhibitor SMIP34 treatment significantly reduced cell viability, invasiveness, colony forming capacity, and induced apoptosis of HCC cells. RNA-seq analyses using PELP1 KD cells confirmed that PELP1 modulates the ribosome and the eukaryotic translation elongation pathways. Mechanistic studies confirmed that SMIP34 treatment contributed to the disruption of the Rix complex, which is crucial for ribosomal biogenesis. Puromycin labelling studies confirmed that PELP1 KD or SMIP34 treatment contributes to the reduction of ribosomal biogenesis and new protein synthesis. Furthermore, PELP1 KD or treatment with SMIP34 dramatically slowed the progression of HCC tumors in xenograft models. IHC analysis revealed reduced levels of the proliferation marker Ki67 in PELP1 KD/SMIP34 treated HCC xenograft tumors compared to controls. Conclusions: Overall, the results of our study point to PELP1 as a potential therapeutic target for HCC intervention. Citation Format: Uday Pratap, Khaled Mohamed Nassar, Xue Yang, Adriana Baker, Rahul Gopalam, William C. Arnold, Timilehin Adeniran, Marian Helena Hernandez Fernandez, Gangadhara R. Sareddy, Suryavathi Viswanadhapalli, Luzhe Sun, Ratna K. Vadlamudi. Significance of PELP1 signaling in liver cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3172.

Abstract Background: Ovarian cancer (OCa) is the deadliest kind of gynecologic cancer in the United States. The long-term survival rate for OCa is less than 20% after five years. Intra-tumoral and inter-tumoral heterogeneity is implicated in tumor resistance to conventional therapies and the unsatisfactory clinical outcomes. Addressing these issues necessitates innovative therapies that target intrinsic common vulnerabilities within OCa. Recent studies have highlighted that high basal level of endoplasmic reticulum stress (ERS) in OCa as a critical vulnerability. We have identified a promising compound, ERX-208 that potently induces ERS in cancer cells. The objective of this study is to characterize the mechanisms and activity of ERX-208 using preclinical models. Methods: The biological activity of ERX-208 was examined across 17 distinct OCa cells, representing 5 diverse OCa subtypes. Mechanistic studies utilized Western blotting, immunohistochemistry (IHC), RNA-Seq analysis, and CRISPR/Cas9 knockouts (KO). Pharmacokinetics (PK) and toxicity studies were performed on C57BL/6 mice. Comprehensive preclinical assessments were carried out through cell line-derived xenografts (CDXs), patient-derived xenografts (PDXs), organoids (PDOs) and explants (PDEs). Results: ERX-208 demonstrated an IC50 of approximately 50-100 nM inducing ERS and reducing cell viability in OCa cells. Conversely, normal ovarian surface epithelial cells exhibited minimal effects from ERX-208. In vitro experiments revealed strong ERX-208-induced apoptosis in OCa cell lines. Mechanistic studies employing RNA sequencing, Western blotting, and RT-qPCR, confirmed activation of ERS pathways observed as early as 5 hours post-ERX-208 treatment. Our studies identified LIPA as a potential target, and KO of LIPA significantly diminished ERX-208 activity. Moreover, LIPA KO substantially impeded in vivo OCa tumor growth. ERX-208 up to a dose of 25 mg/kg showed no observable organ toxicity and had no effect on the mice's body weight. Dose range studies identified 10 mg/kg intraperitoneal as the minimal effective dose, achieving more than 50% tumor reduction. In preclinical models, ERX-208 inhibited the growth of OCa CDXs, PDXs, and ex vivo PDEs and PDO’s. IHC analyses indicated reduced proliferation (Ki-67) and increased activation of ERS markers, such as GRP78 and p-PERK. Conclusions: Collectively, our findings underscore the preclinical promise of ERX-208 as a potential therapeutic agent for treating OCa. Conflict: The patents surrounding ERX-208 are licensed to EtiraRx. Citation Format: Suryavathi Viswanadhapalli, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Henry Neal, Chia-Yuan Chen, Kara Kassees, Christian Cervantes, Zhenming Xu, Edward Kost, Gangadhara Reddy Sareddy, Rajeshwar R. Tekmal, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Preclinical evaluation of ERX-208, a potent inducer of ER stress for the treatment of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 394.

Abstract Background: Inflammatory breast cancer (IBC) is a rare but incredibly aggressive subtype of breast cancer (BC). IBC accounts for 2-4% of all occurrences of breast cancer and results in 7-10% of breast cancer-related deaths. IBC is only partially treatable with current therapies such as chemotherapy, surgery, and radiotherapy. Identification of novel therapeutic targets is urgently required. The main organelle for the synthesis, folding, and modification of proteins is called the endoplasmic reticulum (ER). Since elevated basal ER stress (ERS) is usually found in many cancers including IBC, our hypothesis was that the high basal ERS in IBC constitutes a serious vulnerability that can be targeted. Recently, we developed a small molecule ERX41 that promotes ER stress by blocking Lysosomal acid lipase A (LIPA) function in ER of cancer cells. The goal of the project is to test the utility of ERX-41 in treating IBC. Methods: To study the effect of ERX-41, we have used three well-established IBC model cells. We evaluated the efficacy of ERX-41 as a novel therapeutic for treating IBC using cell viability assays. The long-term effects of ERX-41 on IBC cell survival were evaluated using colony formation assays. Annexin V assays were used to measure apoptosis. Reporter assays, splicing assays, RT-qPCR, and Western blotting were used in mechanistic investigations. The effectiveness of ERX-41 was examined in vivo using KPL4 cell-based xenografts. Results: ERX-41 significantly decreased the viability of all three IBC model cells (SUM149, SUM190PT, and KPL4), with an IC50 of about 125 nM in MTT assay. Additionally, ERX-41 treatment significantly decreased IBC cells capacity to form colonies and promoted apoptosis. Specificity of the ERX41 mediated actions were confirmed using LIPA KO cells. Using RTqPCR based splicing assays, we demonstrated increased splicing of XBP1 as early as 6 hours after ERX41 treatment. Western analyses showed robust induction of stress markers (CHOP, PERK, ATF4) in IBC cells upon treatment with ERX-41. In KPL4 xenograft studies, ERX-41 showed significant reduction in the tumor volume. IHC analyses confirmed decreased proliferation marker and increased ER stress markers. Conclusions: Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of action and implicate ERX-41 binding to LIPA induces ER stress and promotes apoptosis of IBC cells. Citation Format: Zenaida Fuentes, Rahul Gopalam, Bianca A. Romo, Khaled Mohamed Nassar, Xue Yang, Behnam Ebrahimi, Paulina Ramirez, Chia-Yuan Chen, Scott Elmore, Harika Nagandla, Uday Pratap, Christoforos Thomas, Suryavathi Viswanadhapalli, Jung-Mo Ahn, Ganesh Raj, Ratna K. Vadlamudi. Novel LIPA targeted therapy for treating inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2100.

Abstract Abstract 663 Background: The majority of patients with relapsed or refractory B-cell, non-Hodgkin's lymphoma (NHL) are over 60 years of age, yet many are denied potentially curative high-dose regimens due to concerns of excessive toxicity. We have shown that myeloablative anti-CD20 radioimmunotherapy (RIT) can safely deliver effective radiation doses to tumor sites while limiting exposure to normal organs in older adults requiring high-dose therapy, however, not all patients in this series remained progression-free (Gopal, JCO 2007). Preclinical data suggest that improved anti-tumor activity may be attained by the concurrent administration of nucleoside analogs (fludarabine, cytarabine) which synergize with RIT (Johnson, Int J Cancer; Gopal, BBMT, 2006). We hypothesized that a prolonged regimen of fludarabine could be administered concurrently with myeloablative RIT and ASCT to safely augment the efficacy of this approach. We present the phase I data evaluating this strategy. Methods: Patients were eligible if they were 60 years of age or older, had mantle cell lymphoma (MCL) in first remission or relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies (HAMA). All patients underwent outpatient biodistribution studies for dosimetry using tositumomab (1.7 mg/kg, n=3 or 485mg flat dose, n=33) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Patients then received therapeutic infusions of I-131-tositumomab to deliver 27Gy to the critical normal organ receiving the highest radiation exposure. Forty-eight hours later fludarabine was administered in escalating doses to patients (Table) to define a regimen associated with a dose limiting toxicity (DLT = grade III/IV Bearman toxicity) rate of <25%. ASCT occurred when radiation exposure was estimated to be <2mR/hr at 1meter. Filgrastim at 5μg/kg/day or pegfilgrastim at 6mg × 1 was started on day 1. Response was scored using standard criteria. Results: Between July 2005 and May 2011 36 patients were treated. Baseline characteristics included: median age 65 yrs (range 60–76), stage III/IV = 34 (94%), median number of prior regimens = 2 (range 1–9), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 12 (33%), >1 extranodal site = 14 (39%), elevated LDH at treatment = 13 (36%), IPI score at transplant 3–5 = 53%. Histology: MCL = 23, diffuse large B-cell = 8 (with 5 transformed from follicular lymphoma [FL]), FL=3, and marginal zone = 1, Waldenstrom's = 1. Dose limiting organs receiving up to 27Gy included lung (30), kidney (4), and liver (2) with a median administered I-131 activity of 471 mCi (range 260–1620). Fludarabine was escalated from 10 mg/m2/day × 5 days to 30 mg/m2 × 7 days without observation of a DLT (Table). The median CD34 dose was 5.42 ×106/kg with neutrophil (ANC>500μl) and platelet (>20 K/μl) engraftment occurring a median on 10 and 12 days after ASCT, respectively. Only 2 patients developed grade 4 NCI-CTC grade 4 non-hematologic toxicities (hypokalemia/hypophosphatemia, depression), 25 (69%) remained outpatients after discharge from radiation isolation, and there were no non-relapse deaths in the first 100 days after transplant. Responses to therapy were as follows: CR/CRu = 26 (79%), PR = 2 (6%), SD = 4 (11%), and PD = 4 (11%). Currently, 23 (64%) patients are alive with 22 (61%) progression free. The estimated 3 yr overall survival, progression-free survival, relapse, and non-relapse mortality are 54%, 53%, 41%, and 7%, respectively (median follow up of 2.5yrs after ASCT, Figure). Improved survival was associated with <2 prior regimens (HR=.08, p=.02) and chemosensitive disease (HR=.35, p=.07). Conclusions: High-dose (27 Gy) I-131 tositumomab can safely be administered concurrently with up to 210 mg/m2 fludarabine in an older, high-risk patient population. This strategy warrants further investigation as a method to safely augment the antitumor activity of myeloablative RIT. Disclosures: Gopal: GSK: Research Funding; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Piramal: Research Funding; Cephalon: Research Funding; Millenium: Speakers Bureau; Abbott: Research Funding; Pfizer: Research Funding; SBio: Research Funding; Bio Marin: Research Funding; Biogen-Idec: Research Funding. Off Label Use: High-dose use of I-131-tositumomab. Maloney:GSK: Consultancy, Honoraria.

Abstract Background: Of all gynecologic cancers, ovarian cancer (OCa) has the highest mortality rates. Nearly 90% of patients who receive standard surgical and cytotoxic treatment experience disease recurrence. Leukemia inhibitory factor (LIF) and its receptor LIFR are implicated in the progression of several cancers. A knowledge gap exists on whether LIF/LIFR plays a role in the evolution of OCa. We recently developed EC359, a first-in-class LIFR inhibitor. Here, we examined whether autocrine loops of LIF/LIFR contribute to OCa progression and tested the utility of EC359 as a potential targeted therapy. Methods: Eighteen different OCa model cells, both established and primary, were used to profile the expression of LIF and LIFR. Cell viability, colony formation, apoptosis, and reporter assays were used to assess EC359 impact on OCa cells. Mechanistic studies were carried out using RNA-seq and RT-qPCR analysis. Using cell-based xenografts, syngeneic xenografts, patient derived organoids (PDO), and patient derived xenograft (PDX) models, the effectiveness of LIFR inhibitor EC359 as a targeted therapy was examined. Results: Kaplan-Meier survival analysis (KMplot) revealed increased expression of LIF and LIFR was linked to poor progression-free survival in OCa patients. The levels of LIF and LIFR were considerably greater in OCa chemotherapy non-responders than responders. We validated the existence of LIF/LIFR autocrine signaling using 18 distinct OCa cells. Treatment with the LIFR inhibitor EC359 dramatically decreased OCa cell viability, cell survival and increased apoptosis, with an IC50 of 5 to 50 nM. The activation of STAT3, mTOR, AKT, and p42/44 MAPKs as well as other downstream LIFR signaling was markedly decreased by EC359 treatment. Treatment with EC359 also decreased the stemness of OCa cells, slowed PDO development, and sensitized chemotherapy-resistant OCa cells to chemotherapy. One of the significant pathways elevated by EC359, according to RNA-seq data, is the regulation of apoptosis. In six different cell-based xenografts and PDX tumors, we demonstrated that the EC359 at 5mg/kg dose significantly reduced the OCa xenograft growth. In comparison to the vehicle control, the tumor volume was significantly reduced by EC359 treatment of murine ID8 xenografts in C57BL6 mice. Our findings indicated that EC359 had both intrinsic and extrinsic effects on tumors. Tumor-associated macrophages (TAMs) with a significant M1 polarity (CD11b+Gr1-CD68high/phosphoSTAT1+/cMAF-) and robust tumor infiltration by (CD45+) leukocytes were enhanced with EC359 therapy of ID8 xenograft tumors. Importantly, normal T, B, and other immune cells in the blood demonstrated that EC359 had no effect on immune cell homeostasis. Conclusions: Together, our findings support the existence of LIF/LIFR autocrine loops, and EC359 is a viable treatment option for OCa. Citation Format: Behnam Ebrahimi, Suryavathi Viswanadhapalli, Uday P. Pratap, Rahul Gopalam, Xue Yang, Bindhu Santhamma, Swapna Konda, Xiaonan Li, Hui Yan, Gangadhara R. Sareddy, Zhenming Xu, Edward R. Kost, Rajeshwar R. Tekmal, Hareesh B. Nair, Ratna K. Vadlamudi. Targeting LIF/LIFR autocrine loops with EC359 in ovarian cancer: A novel LIFR targeted therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4966.

Abstract Introduction: Of all gynecologic cancers, epithelial ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The potential involvement of leukemia inhibitory factor (LIF) and its receptor (LIFR) in the progression of OCa is still obscure. In this study, we examined the mechanisms by which disruption of LIF/LIFR autocrine loops contributes to the cell death of ovarian cancer cells. Methods: The expression profiles of LIF and LIFR were obtained using 24 distinct OCa model cells, comprising both primary and established cell lines. The effects of EC359 on OCa cells were evaluated using reporter assays, colony formation, cell death, and cell viability. Flow cytometry was utilized to analyze lipid peroxidation. The Agilent Seahorse XF Pro Analyzer was used to calculate the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Furthermore, flow cytometry was used for the preparation and analysis of lymphocytes. Mechanistic investigations were performed with RT-qPCR and RNA-seq analysis. The efficacy of the LIFR inhibitor EC359 as a targeted therapy was investigated using cell-based xenografts, syngeneic xenografts, patient-derived organoids (PDO), and patient-derived xenograft (PDX) models. Results: Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using 24 different primary and established OCa cell lines that represent four subtypes of epithelial OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with EC359, a novel LIFR inhibitor, significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5 to 50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo, and in vivo models including organoids, cell-based xenografts, patient-derived explants, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Conclusions: Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa. Citation Format: Behnam Ebrahimi, Suryavathi Viswanadhapalli, Uday P. Pratap, Rahul Gopalam, Xue Yang, Prabhakar P. Venkata, Viktor Drel, Bindu Santhamma, Swapna Konda, Xiaonan Li, Alondra L. Rodriguez Sanchez, Hui Yan, Gangadhara R. Sareddy, Zhenming Xu, Brij B. Singh, Philip T. Valente, Yidong Chen, Zhao Lai, Manjeet Rao, Edward R. Kost, Tyler Curiel, Rajeshwar R. Tekmal, Hareesh B. Nair, Ratna K. Vadlamudi. Pharmacological inhibition of the LIF-LIFR autocrine loop reveals vulnerability of ovarian cancer to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5998.

Abstract BACKGROUND: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Currently approved therapies have improved OCa survival for clinically localized disease, however, the majority (~90%) of patients with high-grade serous OCa (HGSOC) experience relapse with incurable metastases. There is a dire need for new therapeutic approaches. We hypothesized that the high basal endoplasmic reticulum stress (ERS) in OCa represents a critical and targetable vulnerability and may overcome the tumor heterogeneity. The objective of this project is to exploit increased ERS in ovarian cancer cells by engaging the novel target LIPA using the unique compound ERX-41. METHODS: The utility of ERX-41 as a new therapy was evaluated using MTT and CellTiter-Glo Cell Viability Assays. We used multiple established and patient derived OCa cell lines. The effect of ERX-41 on the Cell viability of patient-derived organoids (PDO) was measured using CellTiter-Glo 3D Assay. Long term effects of ERX-41 on cell survival were measured using colony formation assays. Apoptosis was measured using Annexin V and Caspase-Glo® 3/7 Assays. Cell cycle analysis was analyzed by Flow Cytometry. Mechanistic studies were done using LIPA knockout (KO) cells, RT-qPCR, and western blotting. Status of LIPA in OCa was determined using TNMplot database. In vivo efficacy of ERX-41 was tested using both cell line derived (CDX) and patient derived (PDXs) xenografts. RESULTS: TNM plot results showed that LIPA is highly expressed in OCa tumors compared to normal tissues and LIPA expression correlated with clinical grade. Kaplan-Meier plotter analyses of TCGA data revealed that LIPA expression is negatively correlated with overall survival in OCa patients. MTT and CellTitre-Glo assay results showed that ERX-41 significantly reduced the cell viability of both established and primary OCa cells, and PDO’s with an IC50 of ~500nM. ERX-41 treatment also significantly reduced the cell survival, increased S-phase arrest, and promoted apoptosis of OCa cells. A time course study revealed a robust and consistent induction of ERS markers (CHOP and sXBP1) in OCa cells by ERX-41 within 4h. Western blotting analyses also confirmed increased expression of ERS markers including CHOP, elF2α, PERK, and ATF4 upon ERX-41 treatment confirming that ERX-41 induces ERS. In xenograft studies, ERX-41 treatment resulted in ~66% reduction of tumor volume measured by Xenogen-IVIS. Further, in studies using PDX tumors, treatment with ERX-41 resulted in a significant reduction (~60%) of tumor volume and tumor weight. CONCLUSION: Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of action and implicate ERX-41 binding to LIPA induces ER stress, and apoptosis of OCa cells. Further molecular characterization of how ERX-41 binding to LIPA induces ER stress in OCa cells is ongoing. Citation Format: Alexia B. Collier, Suryavathi Viswanadhapalli, Tae-Kyung Lee, Kara Kassees, Karla Parra, Gaurav Sharma, Tanner Reese, Michael Hsieh, Xihui Liu, Xue Yang, Behnam Ebrahimi, Uday P. Pratap, Rahul Gopalam, Chia Yuan Chen, Scott Terry Elmore, Gangadhara Reddy Sareddy, Edward R. Kost, Jung-Mo Ahn, Ganesh V. Raj, Ratna K. Vadlamudi. Novel LIPA targeted therapy for treating ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3986.

Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Despite initial response to chemotherapy, most OCa patients become chemo resistant and progress to metastatic disease. Here, we tested the hypothesis that the high basal level of endoplasmic reticulum stress (ERS) in OCa represents a critical vulnerability and drugs that further aggravate this already engaged system in OCa may exhaust its protective features and contribute to apoptosis induction. The objective of this proposal is to identify a hit compound that enhances ERS in OCa and to conduct mechanistic studies. Methods: We synthesized a small library of &gt;200 chemically distinct oligobenzamide analogs with maintenance of the chemical backbone but altered R groups of ERX-11. We performed the primary screening of this library to evaluate the induction of mRNA levels of two canonical ERS/UPR (unfolded protein response) genes- sXBP1 and CHOP. Biological activity of ERX-208 was validated using multiple OCa cells. Mechanistic studies were conducted using CRISPR/Cas9 KO, Western blotting, reporter gene assays, IHC and RNA-seq analysis. PK (pharmacokinetics) and toxicity studies were done using C57BL/6 mice. Cell line-derived xenografts (CDXs), patient-derived xenografts (PDXs), patient-derived explants (PDEs), and patient-derived organoids (PDO) were used for preclinical evaluation. Results: From a screen of a curated ERX-11 derived oligobenzamide library, we identified a hit compound, ERX-208 that potently (IC50~100nM) induces ERS/UPR and apoptosis in multiple OCa cells in vitro. CRISPR KO screen identified the lysosomal acid lipase A (LIPA) protein as the critical target of ERX-208. LIPA KO abrogates response to ERX-208, while reconstitution of LIPA restores ERX-208 response. The time course studies showed a robust and consistent induction (&gt;15-fold CHOP, and &gt;10-fold sXBP1) by ERX-208 treatment within 24h. We confirmed induction of classic UPR components peIF2α, CHOP and LC3B using Western blotting in multiple OCa cells. Functionally, ERX-208 causes growth inhibition of OCa cells, as noted by MTT cell viability assays using 15 OCa cells with an IC50 of ~50-100nM. The activity of ERX-208 is distinct among oligobenzamides as ERX-11 has limited/no activity against OCa cells. RNA-seq analysis confirmed that ERX-208 induces significant ERS, UPR, and apoptosis. Further, ERX-208 reduced the growth of OCa PDO’s in vitro, PDEs ex vivo and CDXs and PDXs in vivo. ERX-208 treatment did not show any signs of toxicity and body weight of mice was not affected. IHC analyses showed increased activation of ERS/UPR markers such as GRP78, p-PERK and decreased proliferation measured by Ki67. Conclusions: Collectively, our results demonstrated the utility of ERX-208 and will establish a novel therapeutic paradigm in OCa that overcomes tumor heterogeneity by targeting LIPA and enhancing ERS leading to apoptosis. Citation Format: Suryavathi Viswanadhapalli, Tae-Kyung Lee, Kara Kassees, Gaurav Sharma, Rahul Gopalam, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Chia Yuan Chen, Scott Terry Elmore, Christian Cervantes, Zhenming Xu, Edward Kost, Gangadhara Reddy Sareddy, Rajeshwar Rao Tekmal, Jung-Mo Ann, Ganesh V. Raj, Ratna K. Vadlamudi. ERX-208 as a novel therapeutic for treating ovarian cancer by enhancing endoplasmic reticulum stress. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4813.

Abstract Interferon-gamma (IFNγ)-driven adaptive immune resistance (AIR) in cancer begins at the plasma membrane where cytokine signaling is initiated. Cytotoxic CD8+ T cells secrete IFNγ, eliciting tumor-intrinsic IFNγ signaling and expression of immunosuppressive genes, which are critical for effective therapeutic response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade (ICB). Although the IFNγ receptor (IFNγR) is expressed in all cell types, its surface density can determine a cell’s responsiveness to ligand. Mechanistic control over this process remains a mystery. Herein we report that the endocytic trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR during primary tumor progression and in the setting of ICB therapy. The IFNγR1 subunit of the receptor is constitutively internalized in a ligand-independent manner. ARF6 is necessary for endocytic recycling of IFNγR1 and determines the steady-state surface density of the receptor. Loss of ARF6 results in lysosomal degradation of the receptor and controls IFNγR1 protein levels in melanoma, non-small cell lung cancer, colorectal cancer, and triple-negative breast cancer. IFNγ activates ARF6 in parallel with JAK1-STAT1 signaling, suggesting a positive feedback loop that allows tumor cells to dynamically respond to immune attack. Silencing ARF6 reduces tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to systemic ICB therapy. Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent adaptive immunity, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor shapes clinical outcomes of ICB therapy. Private Information Citation Format: Yinshen Wee, Junhua Wang, Emily C. Wilson, Coulson P. Rich, Aaron Rogers, Zhongzong Tong, Evelyn DeGroot, Y.N. Vashisht Gopal, Michael Davies, Huseyin Atakan Ekiz, Joshua K.H. Tay, Chris Stubben, Kenneth M. Boucher, Juan M. Oviedo, Keke C. Fairfax, Matthew A. Williams, Sheri L. Holmen, Roger K. Wolff, Allie H. Grossmann. ARF6-dependent endocytic trafficking of the interferon-gamma receptor drives adaptive immune resistance and response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3926.

Abstract Background Social isolation or living alone can negatively affect mental health, sleep quality, eating behavior, immunity, proinflammatory response to stress, and receipt of care in cancer patients (e.g., assistance with nutrition and mobility, emotional and informational support), which may increase the risk of death from cancer. Previous studies, however, have shown inconsistent findings on the association between social isolation and cancer mortality. To address the literature gap, we examined this association among working-age adults stratified by sociodemographic characteristics using a nationally representative cohort with long-term mortality follow-up. Method We used the pooled 1998-2019 data for adults aged 18-64 years at enrollment from the National Health Interview Survey (NHIS) linked to National Death Index (N=473,648) with up to 22 years of follow-up. Cox proportional hazards regression was used to model survival time as a function of social isolation, measured by “living alone”, and sociodemographic, behavioral, and health characteristics. We estimated differential effects of social isolation on cancer mortality by age, sex, race/ethnicity, poverty level, and education, overall and for select common cancers (lung, colorectal, and female breast) with &gt;100 deaths in the public use NHIS-linked mortality database, 1998-2004. Results The cancer mortality risk was 32% higher (hazard ratio [HR]=1.32; 95%CI:1.25,1.39) in adults living alone, controlling for age, and 16% higher (HR=1.16; 95%CI:1.10,1.23) in adults living alone, controlling for demographic and socioeconomic characteristics, when compared to adults living with others. The association between living alone and cancer mortality persisted after additional adjustments for health-risk behaviors and health status (HR=1.10, 95%CI:1.04,1.16). Stratified models generally showed similar associations between social isolation and cancer mortality risk across categories of sex, poverty, and education in age-adjusted models. However, the association was stronger among non-Hispanic (NH) White than NH Black adults and did not exist in other racial/ethnic groups. The associations were attenuated after additional adjustments but persisted in fully adjusted models among males, females, NH White people, and adults with a college degree. In the age-adjusted models, social isolation was associated with a higher risk of death from lung (HR=1.45; 95%CI:1.81,2.45) and colorectal (HR=1.65; 95%CI:2.58,1.56), but not from female breast cancer. Conclusions In this nationally representative study in the United States, adults living alone were at a higher risk of cancer death compared to adults living with others. These findings underscore the significance of addressing social isolation in the general population and among cancer survivors. Citation Format: Hyunjung Lee, Gopal K. Singh, Ahmedin Jemal, Farhad Islami. Differential effects of social isolation on cancer mortality by race/ethnicity and socioeconomic status among working age adults in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1927.

The study demonstrated that spatial analysis with relevant socio-economic sources and physical parameter from different sources can be evaluated for the filling station sites planning. This has demonstrated the importance of Geographic Information System (GIS) application in predicting and determining of site criteria for filling stations facilities development, most especially in areas where there is land uses competition which requires consumer accessibility, sustainability, environmental safety, environmentally sensitive development solutions, etc. A stratified sampling technique was used to select the sample size and administration of the questionnaire. The data collected was analyzed using descriptive statistics such as frequency distribution, bar chart, pie chart and percentage and maps showing the sampled existing filling stations in the study area. The result shows the distribution of filling stations located across the study area. This study shows that GIS and multi-criteria analysis are essential tools to assist in correct siting to national planners and decision-makers in deciding the most appropriate filling stations location pattern to apply in Minna and its environs. Keywords: GIS, filling stations, spatial distribution, location, distance. References Aklilu, A., & Necha, T. (2018). Analysis of the spatial accessibility of addis Ababa’s light rail transit: The case of East–West corridor. Urban Rail Transit, 4(1), 35-48. doi:10.1007/s40864-018-0076-6 Dhiman, R., Kalbar, P., & Inamdar, A. B. (2019). Spatial planning of coastal urban areas in india: Current practice versus quantitative approach. Ocean and Coastal Management, 182 doi:10.1016/j.ocecoaman.2019.104929 Tah, D.S (2017). GIS-based locational analysis of Petrol filling stations in Kaduna metropolis: Science World Journal, Vol 12(2): 8-12. Emakoji, M.A., and Otah K.N (2018). Managing Filling Stations Spatial Database using an innovative GIS tool- a case study of Afipko City in Nigeria: Asian Journal of Geographical Research, 1(2):1-9, 2018 Jahangiri, M., Ghaderi, R., Haghani, A., & Nematollahi, O. (2016). Finding the best locations for establishment of solar-wind power stations in middle-east using GIS: A review. Renewable and Sustainable Energy Reviews, 66, 38-52. doi:10.1016/j.rser.2016.07.069 Jelokhani-Niaraki, M., Hajiloo, F., & Samany, N. N. (2019). A web-based public participation GIS for assessing the age-friendliness of cities: A case study in tehran, iran. Cities, 95 doi:10.1016/j.cities.2019.102471 Loidl, M., Witzmann-Müller, U., & Zagel, B. (2019). A spatial framework for planning station-based bike sharing systems. European Transport Research Review, 11(1) doi:10.1186/s12544-019-0347-7 Ma, Y., & Gopal, S. (2018). Geographicallyweighted regression models in estimating median home prices in towns of massachusetts based on an urban sustainability framework. Sustainability (Switzerland), 10(4) doi:10.3390/su10041026 Maanan, M., Maanan, M., Rueff, H., Adouk, N., Zourarah, B., & Rhinane, H. (2018). Assess the human and environmental vulnerability for coastal hazard by using a multi-criteria decision analysis. Human and Ecological Risk Assessment, 24(6), 1642-1658. doi:10.1080/10807039.2017.1421452 Khahro, S. H., Matori, A. N., Chandio, I. A., & Talpur, M. A. H. (2014). Land Suitability Analysis for Installing New Petrol Filling Stations Using GIS. Procedia Engineering, 77, 28–36. doi:10.1016/j.proeng.2014.07.024 Mustapha, O.O (2016). Assessment of filling stations in Illorin, Kwara State, Nigeria using Geospatial technologies, IJSRCSEIT vol 1(2) 69-73, 2016 Naboureh, A., Feizizadeh, B., Naboureh, A., Bian, J., Blaschke, T., Ghorbanzadeh, O., & Moharrami, M. (2019). Traffic accident spatial simulation modeling for planning of road emergency services. ISPRS International Journal of Geo-Information, 8(9) doi:10.3390/ijgi8090371 Peprah (2018). Suitability analysis of siting oil and gas filling station using multi-criteria decision analysis and GIS approach- a case study of Tarkwa and environs- Ghana: Journal of Geomatics, vol 12(2): 158-166, 2018 Sacramento Gutierres, F., Torrente, A. O., & Torrent-Moreno, M. (2019). Responsive geographical information systems for spatio-temporal analysis of mobile networks in barcelona. Architecture, City and Environment, 14(40), 163-192. doi:10.5821/ace.14.40.5349 Vaz, E., Lee, K., Moonilal, V., & Pereira, K. (2018). Potential of geographic information systems for refugee crisis: Syrian refugee relocation in urban habitats. Habitat International, 72, 39-47. doi:10.1016/j.habitatint.2017.02.001 Copyright (c) 2019 Geosfera Indonesia Journal and Department of Geography Education, University of Jember This work is licensed under a Creative Commons Attribution-Share A like 4.0 International License

Abstract Background: Recent advances in the treatment of non-Hodgkin lymphoma (NHL) have transformed the landscape and provided significant benefits to patients. Novel agents that target CD19 and CD20 on B cells, such as bispecific T-cell engagers and chimeric antigen receptor T-cell (CAR-T) therapy, have demonstrated benefit for patients in the relapsed and refractory setting. However, these agents can often be associated with significant toxicity and there is a need for new therapies that can provide clinical benefit with a superior safety profile. Imvotamab is a novel CD20 x CD3 bispecific antibody utilizing an IgM backbone. This allows targeting of up to 10 CD20 binding sites for every CD3 site. In preclinical models, imvotamab demonstrated encouraging antitumor activity and stimulated T-cells in a more physiologic manner than IgG-based antibodies, which may reduce adverse events typically associated with T-cell engagers and CAR-T, such as CRS and neurotoxicity. Loncastuximab tesirine is a CD19-targeting antibody-drug conjugate approved by the US FDA and EMA for relapsed DLBCL after 2 lines of systemic therapy. Loncastuximab tesirine has shown activity in both DLBCL and FL. Combining therapies such as loncastuximab tesirine, which targets CD19 and induce apoptosis of cancer cells, with imvotamab’s ability to eliminate CD20+ tumor cells by engagement with T-cells, may improve treatment outcomes among patients with NHL via synergistic mechanisms of action. Methods: This study is a Phase 1/2, multicenter, single-arm clinical trial of imvotamab as monotherapy and in combination with loncastuximab tesirine for patients with relapsed/refractory NHL. Phase 1a Dose Escalation is complete with no DLTs or neurotoxicity AEs up to 1000mg dose titration. Phase 1b Combination will evaluate imvotamab and loncastuximab tesirine in patients with R/R 2nd line or later NHL. Phase 2 monotherapy Dose Selection is currently ongoing. The Phase 2 component randomizes patients at two different dose levels (100 mg and 300 mg plateau dose) in two separate indications (R/R DLBCL and R/R FL). Patients receive weekly dosing on Day 1, 8, and 15 of each 21- day cycle. Dosing begins at 15 mg and is increased weekly for 3-4 weeks to reach the plateau dose. Patients then stay at the plateau dose until disease progression or unacceptable toxicity. Patients who achieve a response by Week 12 may switch to a less frequent dosing interval of every 3 weeks. Primary endpoints include frequency and severity of adverse events and objective response rate (ORR) based on Lugano criteria. Correlative biomarker studies will evaluate the relationship of clinical benefit with blood and tissue biomarkers. The study is currently open with patients enrolling in Phase 2 at time of submission. Phase 1b Combination is expected to begin enrollment in the first quarter of 2023. Clinical trial information: NCT04082936. Citation Format: Catherine Diefenbach, Won Seog Kim, Chan Cheah, Ajay K. Gopal, Philippe Armand, Ian Flinn, Gareth P. Gregory, Sung-Soo Yoon, Loretta Nastoupil, Jennifer Lue, Vincent Ribrag, Javier Briones, Antonio Salar-Silvestre, Anna Sureda-Balari, Matthew Ku, Hans Cruz, Paul Thaler, Ibrahim Qazi, Rachel Wei, Maya Leabman, Genevive Hernandez, Iris Sison, Elizabeth Budde. A phase 1/2 randomized study of imvotamab monotherapy and in combination with loncastuximab tesirine in relapsed/refractory non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT052.

Abstract Introduction The DAWN study (NCT01779791) evaluated efficacy and safety of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib as monotherapy in relapsed/refractory (R/R) follicular lymphoma (FL) patients (Gopal AK, et al. J Clin Oncol. doi: 10.1200/JCO.2017.76.8853). The overall response rate (ORR) for ibrutinib was 20.9% (95% confidence interval, 13.7-29.7), not meeting the primary end point; however, responders experienced a long duration of response with a median of 19.4 months. We present the results of a biomarker investigation performed on samples from the DAWN study to determine whether somatic mutations could be used to identify FL patients who responded to ibrutinib. Methods DAWN was a multicenter, single-arm, phase 2 study of ibrutinib (560 mg QD) in FL pts with ≥ 2 prior lines of therapy and progressive disease (PD) ≤ 12 months after chemoimmunotherapy (CIT). The primary end point was ORR (complete response [CR] + partial response [PR]). Whole exome sequencing was performed on formalin-fixed, paraffin-embedded tumor samples from 83 patients with available response data - either "responder" (CR + PR; n = 17) or "nonresponder" (stable disease [SD] + PD; n = 66) following ibrutinib treatment. Multiple filters were applied to rule out potential germline variants, and a custom panel of 1216 genes known to be involved in cancer was used for further analysis. Variants enriched in responders or nonresponders were identified using Fisher's exact test. Classifiers were built with variable numbers of genes ranked with a greedy algorithm that selected genes that would, at each iteration, allow the removal of the greatest number of nonresponders from the patient pool, while severely penalizing the removal of responders; classifier performance was assessed using 10-fold cross-validation. Results The overall pattern of variant frequencies identified from the whole exome sequencing in this study was comparable to previously published studies in FL (Krysiak K, et al. Blood. 2017;129:473-483). As there were many more nonresponders than responders in this study, univariate analysis yielded mostly variants significantly enriched in ibrutinib responders but in very low numbers, eg, FANCA, HISTH1B, ANXA6, and PARP10; interestingly, 2 patients with variants in BTG1, which is considered a tumor suppressor, also responded to ibrutinib. Few nonresponder genes were identified in univariate analysis, including NBPF1, ATP6AP1, EP400, and CNOT1; mutations in these genes may activate pathways that bypass BTK, including the mTOR and JAK/STAT pathways. From the selected panel, a 17-gene classifier was developed (Figure) that included variants in ATP6AP1, EP400, ARID1A, SOCS1, TBL1XR1, CNOT1, and KDM2B. Many of these mutated genes have previously been associated with a poor prognosis in cancers, including FL; the biological functions of these genes involve transcription, cell cycle, DNA repair, cell adhesion, protein processing, and transport. Notably, few significant variants emerged that are directly involved in the BTK pathway, unlike previous reports in diffuse large B-cell lymphoma, although, as mentioned above, a few may represent bypass mechanisms to this pathway. Conclusions Mutational analysis of genes in patients from the phase 2 DAWN trial yielded insights into the mechanism of ibrutinib response and resistance in R/R FL. The genes involved in this mechanism demonstrate a large variety of biological functions and show that ibrutinib activity in FL may extend beyond the BTK-NF-kB pathway to gene and protein regulation, DNA repair, adhesion, and other cellular and microenvironmental processes. We have shown previously that its immune activity is also an important mechanism of action in FL (Gopal 2018). A gene-based classifier has been developed that we hypothesize may prove useful in enriching for ibrutinib response in FL; however, this will need to be validated in other data sets. Funding source Sponsored by Janssen Research & Development, LLC. Writing assistance was provided by Jill See of PAREXEL and funded by Janssen Global Services, LLC. Disclosures Balasubramanian: Janssen Research & Development: Employment, Equity Ownership. Hodkinson:Janssen Research & Development: Employment. Schuster:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Trotman:Takeda: Other: unremunerated advisory role; Celgene: Other: unremunerated advisory role; Roche: Other: unremunerated advisory role; Janssen: Consultancy, Research Funding. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Schaffer:Janssen Research & Development: Employment, Equity Ownership. Wang:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment, Equity Ownership. Salles:Gilead: Honoraria, Other: Advisory Board; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Epizyme: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria. Gopal:Teva: Research Funding; Brim: Consultancy; Asana: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Incyte: Consultancy; Spectrum: Research Funding.

Abstract Background High-dose therapy and autologous stem cell transplant (ASCT) remains the standard of care for many high-risk/relapsed B-cell non-Hodgkin lymphomas (B-NHL), T-cell NHL (T-NHL) and classical Hodgkin lymphoma (HL), yet most will not achieve sustained remissions. High-dose anti-CD20 radioimmunotherapy (RIT) and ASCT has been successfully employed to address this challenge in B-NHL, yet relapse still occurs potentially due to blockade of target sites by circulating rituximab (R). RIT options are limited for patients with T-NHL and HL. Preclinical data indicate that targeting the panhematopoietic antigen CD45 with RIT can successfully circumvent R blocking in B-NHL and target a variety of T-NHL histologies (Gopal, 2008 & 2009). We thus performed a phase I trial using high-dose anti-CD45 RIT and ASCT for B-NHL, T-NHL, and HL. Methods Patients were ≥18 years old with relapsed, refractory, or high-risk B-NHL, T-NHL, or HL and had acceptable organ function with an ECOG performance status of 0-1 and no detectible human anti-mouse antibodies. They could not have received ≥20 Gy of prior radiation (RT) to critical organs or prior ASCT within 1 year, or prior allogeneic transplant at any time. All patients first received anti-CD45 antibody (BC8) trace-labeled with 131I followed by gamma camera imaging to evaluate biodistribution and estimate organ-specific absorbed doses. Patients then received 131I-BC8 at an absorbed dose determined by the following: Patients with prior RT >20 Gy or prior ASCT started at 10 Gy to the dose-limiting normal organ (Arm A), while others started dose escalation at 20 Gy (Arm B). Subsequent dose escalation/de-escalation followed a two-stage approach (Storer, 2001). ASCT occurred after sufficient radiation decay, and G-CSF was started on day 1. Dose limiting toxicity (DLT) was determined by Bearman grade III/IV events. The primary objective was to estimate the maximum tolerated dose, defined as that yielding a DLT rate of 25%. Responses were scored using standard criteria (Cheson, 2007). Results Between August 2009 and March 2013, 15 patients were treated. Median age was 62 years (range 20-71); stage III/IV = 11 (73%); median prior regimens = 3 (range 2-12), including 1 prior ASCT; chemorefractory disease (i.e., <PR to the most recent chemotherapy) = 8 (53%); histologies were HL (n = 6), B-NHL (n = 6), and T-NHL (n = 3; see Table). The mean administered 131I activity was 646 mCi (range 344-1064 mCi; 23.9 GBq, range 12.7-39.4 GBq). The liver was the dose-limiting normal organ in 12 patients (2.41-3.98 cGy/mCi). The absorbed dose was escalated to 14 Gy for patients in Arm A (n = 3) and 30 Gy in Arm B (n = 12). Neutrophil (>500/μl) and platelet (>20 K/μl) engraftment occurred a median of 8 (range 10-20) and 12 (range 8-26) days after ASCT, respectively. No DLTs, non-relapse deaths, or non-hematologic toxicities > NCI-CTCAE v3 grade 3 have been observed. Currently, 11 (73%) patients are alive and 7 (47%) are progression-free with a median follow-up of 12 months. Seven (54%) of 13 patients with measurable disease at enrollment had objective disease responses, including 3 of 3 with T-NHL, 3 of 6 with HL, and 1 of 1 with follicular lymphoma (FL; see Table). Conclusion Myeloablative doses of 131I targeted to CD45 are safe and feasible in patients with lymphoma, with no DLTs observed after delivery of up to 30 Gy to the liver. Objective disease responses in heavily-treated B-NHL, T-NHL, and HL were observed. This work has led to current studies using yttrium-90 as the therapeutic radionuclide (given its longer beta pathlength and absence of gamma emission) in anti-CD45 RIT for lymphoma. Disclosures: No relevant conflicts of interest to declare.

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. First generation BTK inhibitor ibrutinib has limited activity as monotherapy in R/R FL (Gopal et al. J Clin Oncol 2018). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic (PK) and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may also be co-administered with strong or moderate CYP3A inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. In preclinical studies, zanubrutinib had minimal inhibitory effects against ITK and did not inhibit ITK-mediated anti-CD20-induced antibody-dependent cell-mediated cytotoxicity (Li et al. Cancer Res 2015). Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients (pts) with either non-Hodgkin lymphoma (NHL), Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib was generally well tolerated amongst pts with B cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1b dose-escalation study including 36 pts with R/R FL (median 2 [range, 1-9] prior lines of therapy) treated with the combination of zanubrutinib with anti-CD20 antibody obinutuzumab reported an overall response rate (ORR) of 72.2% including complete response in 14 pts (38.9%); median progression-free survival was 24.9 mo (Tam et al. ICML 2019). Study Design and Methods: This ongoing phase 2, global, randomized, open-label, active-controlled study (ROSEWOOD; NCT03332017) is examining zanubrutinib + obinutuzumab vs. obinutuzumab monotherapy in pts with R/R FL who have received ≥2 prior lines of therapy (Figure). Eligible pts must have histologically-confirmed grade 1-3a B-cell FL and measurable disease, and have received prior anti-CD20 antibody and alkylator-based combination therapy. Pts are randomized 2:1 to receive oral zanubrutinib 160 mg twice daily + obinutuzumab or obinutuzumab alone (both arms in 28-day cycles, at 1000 mg IV on days 1, 8, and 15 of cycle 1; day 1 of cycles 2-6; and then once every 8 weeks) until progressive disease (PD), toxicity or a maximum of 30 mo of obinutuzumab. Pts receiving zanubrutinib should remain on study treatment until PD. Randomization is stratified by prior therapies (2-3 vs >3) and rituximab-refractory status. Disease response is assessed per the 2014 Lugano Classification for NHL. The primary endpoint is ORR by independent review committee (IRC). Response rates will be compared between groups in an intent-to-treat analysis. Key secondary endpoints include ORR by investigator assessment, rate of complete response or complete metabolic response, time to and duration of response, progression-free survival (all IRC and investigator assessments), overall survival, and safety. At the investigator's discretion, pts in the obinutuzumab arm can cross over to the combination arm if they have PD at any time or less than partial response after 12 mo. Recruitment is ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trotman:Celgene: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Janssen: Research Funding. Auer:Hartley Taylor: Honoraria; Janssen: Honoraria, Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees; Celgene: Other: personal fees. Flowers:TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Bayer: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Optimum Rx: Consultancy; Eastern Cooperative Oncology Group: Research Funding. Reed:BeiGene: Employment, Equity Ownership, Other: Travel & Accommodations. Ivanova:BeiGene: Employment. Huang:BeiGene: Employment, Equity Ownership. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

Climate change induced sea-level rise (SLR) is on its increase globally. Regionally the lowlands of China, Vietnam, Bangladesh, and islands of the Malaysian, Indonesian and Philippine archipelagos are among the world’s most threatened regions. Sea-level rise has major impacts on the ecosystems and society. It threatens coastal populations, economic activities, and fragile ecosystems as mangroves, coastal salt-marches and wetlands. This paper provides a summary of the current state of knowledge of sea level-rise and its effects on both human and natural ecosystems. The focus is on coastal urban areas and low lying deltas in South-East Asia and Vietnam, as one of the most threatened areas in the world. About 3 mm per year reflects the growing consensus on the average SLR worldwide. The trend speeds up during recent decades. The figures are subject to local, temporal and methodological variation. In Vietnam the average values of 3.3 mm per year during the 1993-2014 period are above the worldwide average. Although a basic conceptual understanding exists that the increasing global frequency of the strongest tropical cyclones is related with the increasing temperature and SLR, this relationship is insufficiently understood. Moreover the precise, complex environmental, economic, social, and health impacts are currently unclear. SLR, storms and changing precipitation patterns increase flood risks, in particular in urban areas. Part of the current scientific debate is on how urban agglomeration can be made more resilient to flood risks. Where originally mainly technical interventions dominated this discussion, it becomes increasingly clear that proactive special planning, flood defense, flood risk mitigation, flood preparation, and flood recovery are important, but costly instruments. Next to the main focus on SLR and its effects on resilience, the paper reviews main SLR associated impacts: Floods and inundation, salinization, shoreline change, and effects on mangroves and wetlands. The hazards of SLR related floods increase fastest in urban areas. This is related with both the increasing surface major cities are expected to occupy during the decades to come and the increasing coastal population. In particular Asia and its megacities in the southern part of the continent are increasingly at risk. The discussion points to complexity, inter-disciplinarity, and the related uncertainty, as core characteristics. An integrated combination of mitigation, adaptation and resilience measures is currently considered as the most indicated way to resist SLR today and in the near future.References Aerts J.C.J.H., Hassan A., Savenije H.H.G., Khan M.F., 2000. Using GIS tools and rapid assessment techniques for determining salt intrusion: Stream a river basin management instrument. Physics and Chemistry of the Earth, Part B: Hydrology, Oceans and Atmosphere, 25, 265-273. Doi: 10.1016/S1464-1909(00)00014-9. Alongi D.M., 2002. Present state and future of the world’s mangrove forests. Environmental Conservation, 29, 331-349. Doi: 10.1017/S0376892902000231 Alongi D.M., 2015. The impact of climate change on mangrove forests. Curr. Clim. Change Rep., 1, 30-39. Doi: 10.1007/s404641-015-0002-x. Anderson F., Al-Thani N., 2016. Effect of sea level rise and groundwater withdrawal on seawater intrusion in the Gulf Coast aquifer: Implications for agriculture. Journal of Geoscience and Environment Protection, 4, 116-124. Doi: 10.4236/gep.2016.44015. Anguelovski I., Chu E., Carmin J., 2014. Variations in approaches to urban climate adaptation: Experiences and experimentation from the global South. Global Environmental Change, 27, 156-167. Doi: 10.1016/j.gloenvcha.2014.05.010. Arustienè J., Kriukaitè J., Satkunas J., Gregorauskas M., 2013. Climate change and groundwater - From modelling to some adaptation means in example of Klaipèda region, Lithuania. In: Climate change adaptation in practice. P. Schmidt-Thomé, J. Klein Eds. John Wiley and Sons Ltd., Chichester, UK., 157-169. Bamber J.L., Aspinall W.P., Cooke R.M., 2016. A commentary on “how to interpret expert judgement assessments of twenty-first century sea-level rise” by Hylke de Vries and Roderik S.W. Van de Wal. Climatic Change, 137, 321-328. Doi: 10.1007/s10584-016-1672-7. Barnes C., 2014. Coastal population vulnerability to sea level rise and tropical cyclone intensification under global warming. BSc-thesis. Department of Geography, University of Lethbridge, Alberta Canada. Be T.T., Sinh B.T., Miller F., 2007. Challenges to sustainable development in the Mekong Delta: Regional and national policy issues and research needs. The Sustainable Mekong Research Network, Bangkok, Thailand, 1-210. Bellard C., Leclerc C., Courchamp F., 2014. Impact of sea level rise on 10 insular biodiversity hotspots. Global Ecology and Biogeography, 23, 203-212. Doi: 10.1111/geb.12093. Berg H., Söderholm A.E., Sönderström A.S., Nguyen Thanh Tam, 2017. Recognizing wetland ecosystem services for sustainable rice farming in the Mekong delta, Vietnam. Sustainability Science, 12, 137-154. Doi: 10.1007/s11625-016-0409-x. Bilskie M.V., Hagen S.C., Medeiros S.C., Passeri D.L., 2014. Dynamics of sea level rise and coastal flooding on a changing landscape. Geophysical Research Letters, 41, 927-934. Doi: 10.1002/2013GL058759. Binh T.N.K.D., Vromant N., Hung N.T., Hens L., Boon E.K., 2005. Land cover changes between 1968 and 2003 in Cai Nuoc, Ca Mau penisula, Vietnam. Environment, Development and Sustainability, 7, 519-536. Doi: 10.1007/s10668-004-6001-z. Blankespoor B., Dasgupta S., Laplante B., 2014. Sea-level rise and coastal wetlands. Ambio, 43, 996- 005.Doi: 10.1007/s13280-014-0500-4. Brockway R., Bowers D., Hoguane A., Dove V., Vassele V., 2006. A note on salt intrusion in funnel shaped estuaries: Application to the Incomati estuary, Mozambique.Estuarine, Coastal and Shelf Science, 66, 1-5. Doi: 10.1016/j.ecss.2005.07.014. Cannaby H., Palmer M.D., Howard T., Bricheno L., Calvert D., Krijnen J., Wood R., Tinker J., Bunney C., Harle J., Saulter A., O’Neill C., Bellingham C., Lowe J., 2015. Projected sea level rise and changes in extreme storm surge and wave events during the 21st century in the region of Singapore. Ocean Sci. Discuss, 12, 2955-3001. Doi: 10.5194/osd-12-2955-2015. Carraro C., Favero A., Massetti E., 2012. Investment in public finance in a green, low carbon economy. Energy Economics, 34, S15-S18. Castan-Broto V., Bulkeley H., 2013. A survey ofurban climate change experiments in 100 cities. Global Environmental Change, 23, 92-102. Doi: 10.1016/j.gloenvcha.2012.07.005. Cazenave A., Le Cozannet G., 2014. Sea level rise and its coastal impacts. GeoHealth, 2, 15-34. Doi: 10.1002/2013EF000188. Chu M.L., Guzman J.A., Munoz-Carpena R., Kiker G.A., Linkov I., 2014. A simplified approach for simulating changes in beach habitat due to the combined effects of long-term sea level rise, storm erosion and nourishment. Environmental modelling and software, 52, 111-120. Doi.org/10.1016/j.envcsoft.2013.10.020. Church J.A. et al., 2013. Sea level change. In: Climate change 2013: The physical science basis. Contribution of working group I to the fifth assessment report of Intergovernmental Panel on Climate Change. Eds: Stocker T.F., Qin D., Plattner G.-K., Tignor M., Allen S.K., Boschung J., Nauels A., Xia Y., Bex V., Midgley P.M., Cambridge University Press, Cambridge, UK. Connell J., 2016. Last days of the Carteret Islands? Climate change, livelihoods and migration on coral atolls. Asia Pacific Viewpoint, 57, 3-15. Doi: 10.1111/apv.12118. Dasgupta S., Laplante B., Meisner C., Wheeler, Yan J., 2009. The impact of sea level rise on developing countries: A comparative analysis. Climatic Change, 93, 379-388. Doi: 10.1007/s 10584-008-9499-5. Delbeke J., Vis P., 2015. EU climate policy explained, 136p. Routledge, Oxon, UK. DiGeorgio M., 2015. Bargaining with disaster: Flooding, climate change, and urban growth ambitions in QuyNhon, Vietnam. Public Affairs, 88, 577-597. Doi: 10.5509/2015883577. Do Minh Duc, Yasuhara K., Nguyen Manh Hieu, 2015. Enhancement of coastal protection under the context of climate change: A case study of Hai Hau coast, Vietnam. Proceedings of the 10th Asian Regional Conference of IAEG, 1-8. Do Minh Duc, Yasuhara K., Nguyen Manh Hieu, Lan Nguyen Chau, 2017. Climate change impacts on a large-scale erosion coast of Hai Hau district, Vietnam and the adaptation. Journal of Coastal Conservation, 21, 47-62. Donner S.D., Webber S., 2014. Obstacles to climate change adaptation decisions: A case study of sea level rise; and coastal protection measures in Kiribati. Sustainability Science, 9, 331-345. Doi: 10.1007/s11625-014-0242-z. Driessen P.P.J., Hegger D.L.T., Bakker M.H.N., Van Renswick H.F.M.W., Kundzewicz Z.W., 2016. Toward more resilient flood risk governance. Ecology and Society, 21, 53-61. Doi: 10.5751/ES-08921-210453. Duangyiwa C., Yu D., Wilby R., Aobpaet A., 2015. Coastal flood risks in the Bangkok Metropolitan region, Thailand: Combined impacts on land subsidence, sea level rise and storm surge. American Geophysical Union, Fall meeting 2015, abstract#NH33C-1927. Duarte C.M., Losada I.J., Hendriks I.E., Mazarrasa I., Marba N., 2013. The role of coastal plant communities for climate change mitigation and adaptation. Nature Climate Change, 3, 961-968. Doi: 10.1038/nclimate1970. Erban L.E., Gorelick S.M., Zebker H.A., 2014. Groundwater extraction, land subsidence, and sea-level rise in the Mekong Delta, Vietnam. Environmental Research Letters, 9, 1-20. Doi: 10.1088/1748-9326/9/8/084010. FAO - Food and Agriculture Organisation, 2007.The world’s mangroves 1980-2005. FAO Forestry Paper, 153, Rome, Italy. Farbotko C., 2010. Wishful sinking: Disappearing islands, climate refugees and cosmopolitan experimentation. Asia Pacific Viewpoint, 51, 47-60. Doi: 10.1111/j.1467-8373.2010.001413.x. Goltermann D., Ujeyl G., Pasche E., 2008. Making coastal cities flood resilient in the era of climate change. Proceedings of the 4th International Symposium on flood defense: Managing flood risk, reliability and vulnerability, 148-1-148-11. Toronto, Canada. Gong W., Shen J., 2011. The response of salt intrusion to changes in river discharge and tidal mixing during the dry season in the Modaomen Estuary, China.Continental Shelf Research, 31, 769-788. Doi: 10.1016/j.csr.2011.01.011. Gosian L., 2014. Protect the world’s deltas. Nature, 516, 31-34. Graham S., Barnett J., Fincher R., Mortreux C., Hurlimann A., 2015. Towards fair outcomes in adaptation to sea-level rise. Climatic Change, 130, 411-424. Doi: 10.1007/s10584-014-1171-7. COASTRES-D-12-00175.1. Güneralp B., Güneralp I., Liu Y., 2015. Changing global patterns of urban expoàsure to flood and drought hazards. Global Environmental Change, 31, 217-225. Doi: 10.1016/j.gloenvcha.2015.01.002. Hallegatte S., Green C., Nicholls R.J., Corfee-Morlot J., 2013. Future flood losses in major coastal cities. Nature Climate Change, 3, 802-806. Doi: 10.1038/nclimate1979. Hamlington B.D., Strassburg M.W., Leben R.R., Han W., Nerem R.S., Kim K.-Y., 2014. Uncovering an anthropogenic sea-level rise signal in the Pacific Ocean. Nature Climate Change, 4, 782-785. Doi: 10.1038/nclimate2307. Hashimoto T.R., 2001. Environmental issues and recent infrastructure development in the Mekong Delta: Review, analysis and recommendations with particular reference to large-scale water control projects and the development of coastal areas. Working paper series (Working paper No. 4). Australian Mekong Resource Centre, University of Sydney, Australia, 1-70. Hibbert F.D., Rohling E.J., Dutton A., Williams F.H., Chutcharavan P.M., Zhao C., Tamisiea M.E., 2016. Coral indicators of past sea-level change: A global repository of U-series dated benchmarks. Quaternary Science Reviews, 145, 1-56. Doi: 10.1016/j.quascirev.2016.04.019. Hinkel J., Lincke D., Vafeidis A., Perrette M., Nicholls R.J., Tol R.S.J., Mazeion B., Fettweis X., Ionescu C., Levermann A., 2014. Coastal flood damage and adaptation costs under 21st century sea-level rise. Proceedings of the National Academy of Sciences, 111, 3292-3297. Doi: 10.1073/pnas.1222469111. Hinkel J., Nicholls R.J., Tol R.S.J., Wang Z.B., Hamilton J.M., Boot G., Vafeidis A.T., McFadden L., Ganapolski A., Klei R.J.Y., 2013. A global analysis of erosion of sandy beaches and sea level rise: An application of DIVA. Global and Planetary Change, 111, 150-158. Doi: 10.1016/j.gloplacha.2013.09.002. Huong H.T.L., Pathirana A., 2013. Urbanization and climate change impacts on future urban flooding in Can Tho city, Vietnam. Hydrol. Earth Syst. Sci., 17, 379-394. Doi: 10.5194/hess-17-379-2013. Hurlimann A., Barnett J., Fincher R., Osbaldiston N., Montreux C., Graham S., 2014. Urban planning and sustainable adaptation to sea-level rise. Landscape and Urban Planning, 126, 84-93. Doi: 10.1016/j.landurbplan.2013.12.013. IMHEN-Vietnam Institute of Meteorology, Hydrology and Environment, 2011. Climate change vulnerability and risk assessment study for Ca Mau and KienGiang provinces, Vietnam. Hanoi, Vietnam Institute of Meteorology, Hydrology and Environment (IMHEN), 250p. IMHEN-Vietnam Institute of Meteorology, Hydrology and Environment, Ca Mau PPC, 2011. Climate change impact and adaptation study in The Mekong Delta - Part A: Ca Mau Atlas. Hanoi, Vietnam: Institute of Meteorology, Hydrology and Environment (IMHEN), 48p. IPCC-Intergovernmental Panel on Climate Change, 2014. Fifth assessment report. Cambridge University Press, Cambridge, UK. Jevrejeva S., Jackson L.P., Riva R.E.M., Grinsted A., Moore J.C., 2016. Coastal sea level rise with warming above 2°C. Proceedings of the National Academy of Sciences, 113, 13342-13347. Doi: 10.1073/pnas.1605312113. Junk W.J., AN S., Finlayson C.M., Gopal B., Kvet J., Mitchell S.A., Mitsch W.J., Robarts R.D., 2013. Current state of knowledge regarding the world’s wetlands and their future under global climate change: A synthesis. Aquatic Science, 75, 151-167. Doi: 10.1007/s00027-012-0278-z. Jordan A., Rayner T., Schroeder H., Adger N., Anderson K., Bows A., Le Quéré C., Joshi M., Mander S., Vaughan N., Whitmarsh L., 2013. Going beyond two degrees? The risks and opportunities of alternative options. Climate Policy, 13, 751-769. Doi: 10.1080/14693062.2013.835705. Kelly P.M., Adger W.N., 2000. Theory and practice in assessing vulnerability to climate change and facilitating adaptation. Climatic Change, 47, 325-352. Doi: 10.1023/A:1005627828199. Kirwan M.L., Megonigal J.P., 2013. Tidal wetland stability in the face of human impacts and sea-level rice. Nature, 504, 53-60. Doi: 10.1038/nature12856. Koerth J., Vafeidis A.T., Hinkel J., Sterr H., 2013. What motivates coastal households to adapt pro actively to sea-level rise and increased flood risk? Regional Environmental Change, 13, 879-909. Doi: 10.1007/s10113-12-399-x. Kontgis K., Schneider A., Fox J;,Saksena S., Spencer J.H., Castrence M., 2014. Monitoring peri urbanization in the greater Ho Chi Minh City metropolitan area. Applied Geography, 53, 377-388. Doi: 10.1016/j.apgeogr.2014.06.029. Kopp R.E., Horton R.M., Little C.M., Mitrovica J.X., Oppenheimer M., Rasmussen D.J., Strauss B.H., Tebaldi C., 2014. Probabilistic 21st and 22nd century sea-level projections at a global network of tide-gauge sites. Earth’s Future, 2, 383-406. Doi: 10.1002/2014EF000239. Kuenzer C., Bluemel A., Gebhardt S., Quoc T., Dech S., 2011. Remote sensing of mangrove ecosystems: A review.Remote Sensing, 3, 878-928. Doi: 10.3390/rs3050878. Lacerda G.B.M., Silva C., Pimenteira C.A.P., Kopp Jr. R.V., Grumback R., Rosa L.P., de Freitas M.A.V., 2013. Guidelines for the strategic management of flood risks in industrial plant oil in the Brazilian coast: Adaptive measures to the impacts of sea level rise. Mitigation and Adaptation Strategies for Global Change, 19, 104-1062. Doi: 10.1007/s11027-013-09459-x. Lam Dao Nguyen, Pham Van Bach, Nguyen Thanh Minh, Pham Thi Mai Thy, Hoang Phi Hung, 2011. Change detection of land use and river bank in Mekong Delta, Vietnam using time series remotely sensed data. Journal of Resources and Ecology, 2, 370-374. Doi: 10.3969/j.issn.1674-764x.2011.04.011. Lang N.T., Ky B.X., Kobayashi H., Buu B.C., 2004. Development of salt tolerant varieties in the Mekong delta. JIRCAS Project, Can Tho University, Can Tho, Vietnam, 152. Le Cozannet G., Rohmer J., Cazenave A., Idier D., Van de Wal R., de Winter R., Pedreros R., Balouin Y., Vinchon C., Oliveros C., 2015. Evaluating uncertainties of future marine flooding occurrence as sea-level rises. Environmental Modelling and Software, 73, 44-56. Doi: 10.1016/j.envsoft.2015.07.021. Le Cozannet G., Manceau J.-C., Rohmer J., 2017. Bounding probabilistic sea-level projections with the framework of the possible theory. Environmental Letters Research, 12, 12-14. Doi.org/10.1088/1748-9326/aa5528.Chikamoto Y., 2014. Recent Walker circulation strengthening and Pacific cooling amplified by Atlantic warming. Nature Climate Change, 4, 888-892. Doi: 10.1038/nclimate2330. Lovelock C.E., Cahoon D.R., Friess D.A., Gutenspergen G.R., Krauss K.W., Reef R., Rogers K., Saunders M.L., Sidik F., Swales A., Saintilan N., Le Xuan Tuyen, Tran Triet, 2015. The vulnerability of Indo-Pacific mangrove forests to sea-level rise. Nature, 526, 559-563. Doi: 10.1038/nature15538. MA Millennium Ecosystem Assessment, 2005. Ecosystems and human well-being: Current state and trends. Island Press, Washington DC, 266p. Masterson J.P., Fienen M.N., Thieler E.R., Gesch D.B., Gutierrez B.T., Plant N.G., 2014. Effects of sea level rise on barrier island groundwater system dynamics - ecohydrological implications. Ecohydrology, 7, 1064-1071. Doi: 10.1002/eco.1442. McGanahan G., Balk D., Anderson B., 2007. The rising tide: Assessing the risks of climate changes and human settlements in low elevation coastal zones.Environment and urbanization, 19, 17-37. Doi: 10.1177/095624780707960. McIvor A., Möller I., Spencer T., Spalding M., 2012. Reduction of wind and swell waves by mangroves. The Nature Conservancy and Wetlands International, 1-27. Merryn T., Pidgeon N., Whitmarsh L., Ballenger R., 2016. Expert judgements of sea-level rise at the local scale. Journal of Risk Research, 19, 664-685. Doi.org/10.1080/13669877.2015.1043568. Monioudi I.N., Velegrakis A.F., Chatzipavlis A.E., Rigos A., Karambas T., Vousdoukas M.I., Hasiotis T., Koukourouvli N., Peduzzi P., Manoutsoglou E., Poulos S.E., Collins M.B., 2017. Assessment of island beach erosion due to sea level rise: The case of the Aegean archipelago (Eastern Mediterranean). Nat. Hazards Earth Syst. Sci., 17, 449-466. Doi: 10.5194/nhess-17-449-2017. MONRE - Ministry of Natural Resources and Environment, 2016. Scenarios of climate change and sea level rise for Vietnam. Publishing House of Environmental Resources and Maps Vietnam, Hanoi, 188p. Montz B.E., Tobin G.A., Hagelman III R.R., 2017. Natural hazards. Explanation and integration. The Guilford Press, NY, 445p. Morgan L.K., Werner A.D., 2014. Water intrusion vulnerability for freshwater lenses near islands. Journal of Hydrology, 508, 322-327. Doi: 10.1016/j.jhydrol.2013.11.002. Muis S., Güneralp B., Jongman B., Aerts J.C.H.J., Ward P.J., 2015. Science of the Total Environment, 538, 445-457. Doi: 10.1016/j.scitotenv.2015.08.068. Murray N.J., Clemens R.S., Phinn S.R., Possingham H.P., Fuller R.A., 2014. Tracking the rapid loss of tidal wetlands in the Yellow Sea. Frontiers in Ecology and Environment, 12, 267-272. Doi: 10.1890/130260. Neumann B., Vafeidis A.T., Zimmermann J., Nicholls R.J., 2015a. Future coastal population growth and exposure to sea-level rise and coastal flooding. A global assessment. Plos One, 10, 1-22. Doi: 10.1371/journal.pone.0118571. Nguyen A. Duoc, Savenije H. H., 2006. Salt intrusion in multi-channel estuaries: a case study in the Mekong Delta, Vietnam. Hydrology and Earth System Sciences Discussions, European Geosciences Union, 10, 743-754. Doi: 10.5194/hess-10-743-2006. Nguyen An Thinh, Nguyen Ngoc Thanh, Luong Thi Tuyen, Luc Hens, 2017. Tourism and beach erosion: Valuing the damage of beach erosion for tourism in the Hoi An, World Heritage site. Journal of Environment, Development and Sustainability. Nguyen An Thinh, Luc Hens (Eds.), 2018. Human ecology of climate change associated disasters in Vietnam: Risks for nature and humans in lowland and upland areas. Springer Verlag, Berlin.Nguyen An Thinh, Vu Anh Dung, Vu Van Phai, Nguyen Ngoc Thanh, Pham Minh Tam, Nguyen Thi Thuy Hang, Le Trinh Hai, Nguyen Viet Thanh, Hoang Khac Lich, Vu Duc Thanh, Nguyen Song Tung, Luong Thi Tuyen, Trinh Phuong Ngoc, Luc Hens, 2017. Human ecological effects of tropical storms in the coastal area of Ky Anh (Ha Tinh, Vietnam). Environ Dev Sustain, 19, 745-767. Doi: 10.1007/s/10668-016-9761-3. Nguyen Van Hoang, 2017. Potential for desalinization of brackish groundwater aquifer under a background of rising sea level via salt-intrusion prevention river gates in the coastal area of the Red River delta, Vietnam. Environment, Development and Sustainability. Nguyen Tho, Vromant N., Nguyen Thanh Hung, Hens L., 2008. Soil salinity and sodicity in a shrimp farming coastal area of the Mekong Delta, Vietnam. Environmental Geology, 54, 1739-1746. Doi: 10.1007/s00254-007-0951-z. Nguyen Thang T.X., Woodroffe C.D., 2016. Assessing relative vulnerability to sea-level rise in the western part of the Mekong River delta. Sustainability Science, 11, 645-659. Doi: 10.1007/s11625-015-0336-2. Nicholls N.N., Hoozemans F.M.J., Marchand M., Analyzing flood risk and wetland losses due to the global sea-level rise: Regional and global analyses.Global Environmental Change, 9, S69-S87. Doi: 10.1016/s0959-3780(99)00019-9. Phan Minh Thu, 2006. Application of remote sensing and GIS tools for recognizing changes of mangrove forests in Ca Mau province. In Proceedings of the International Symposium on Geoinformatics for Spatial Infrastructure Development in Earth and Allied Sciences, Ho Chi Minh City, Vietnam, 9-11 November, 1-17. Reise K., 2017. Facing the third dimension in coastal flatlands.Global sea level rise and the need for coastal transformations. Gaia, 26, 89-93. Renaud F.G., Le Thi Thu Huong, Lindener C., Vo Thi Guong, Sebesvari Z., 2015. Resilience and shifts in agro-ecosystems facing increasing sea-level rise and salinity intrusion in Ben Tre province, Mekong Delta. Climatic Change, 133, 69-84. Doi: 10.1007/s10584-014-1113-4. Serra P., Pons X., Sauri D., 2008. Land cover and land use in a Mediterranean landscape. Applied Geography, 28, 189-209. Shearman P., Bryan J., Walsh J.P., 2013.Trends in deltaic change over three decades in the Asia-Pacific Region. Journal of Coastal Research, 29, 1169-1183. Doi: 10.2112/JCOASTRES-D-12-00120.1. SIWRR-Southern Institute of Water Resources Research, 2016. Annual Report. Ministry of Agriculture and Rural Development, Ho Chi Minh City, 1-19. Slangen A.B.A., Katsman C.A., Van de Wal R.S.W., Vermeersen L.L.A., Riva R.E.M., 2012. Towards regional projections of twenty-first century sea-level change based on IPCC RES scenarios. Climate Dynamics, 38, 1191-1209. Doi: 10.1007/s00382-011-1057-6. Spencer T., Schuerch M., Nicholls R.J., Hinkel J., Lincke D., Vafeidis A.T., Reef R., McFadden L., Brown S., 2016. Global coastal wetland change under sea-level rise and related stresses: The DIVA wetland change model. Global and Planetary Change, 139, 15-30. Doi:10.1016/j.gloplacha.2015.12.018. Stammer D., Cazenave A., Ponte R.M., Tamisiea M.E., 2013. Causes of contemporary regional sea level changes. Annual Review of Marine Science, 5, 21-46. Doi: 10.1146/annurev-marine-121211-172406. Tett P., Mee L., 2015. Scenarios explored with Delphi. In: Coastal zones ecosystems services. Eds., Springer, Berlin, Germany, 127-144. Tran Hong Hanh, 2017. Land use dynamics, its drivers and consequences in the Ca Mau province, Mekong delta, Vietnam. PhD dissertation, 191p. VUBPRESS Brussels University Press, ISBN 9789057186226, Brussels, Belgium. Tran Thuc, Nguyen Van Thang, Huynh Thi Lan Huong, Mai Van Khiem, Nguyen Xuan Hien, Doan Ha Phong, 2016. Climate change and sea level rise scenarios for Vietnam. Ministry of Natural resources and Environment. Hanoi, Vietnam. Tran Hong Hanh, Tran Thuc, Kervyn M., 2015. Dynamics of land cover/land use changes in the Mekong Delta, 1973-2011: A remote sensing analysis of the Tran Van Thoi District, Ca Mau province, Vietnam. Remote Sensing, 7, 2899-2925. Doi: 10.1007/s00254-007-0951-z Van Lavieren H., Spalding M., Alongi D., Kainuma M., Clüsener-Godt M., Adeel Z., 2012. Securing the future of Mangroves. The United Nations University, Okinawa, Japan, 53, 1-56. Water Resources Directorate. Ministry of Agriculture and Rural Development, 2016. Available online: http://www.tongcucthuyloi.gov.vn/Tin-tuc-Su-kien/Tin-tuc-su-kien-tong-hop/catid/12/item/2670/xam-nhap-man-vung-dong-bang-song-cuu-long--2015---2016---han-han-o-mien-trung--tay-nguyen-va-giai-phap-khac-phuc. Last accessed on: 30/9/2016. Webster P.J., Holland G.J., Curry J.A., Chang H.-R., 2005. Changes in tropical cyclone number, duration, and intensity in a warming environment. Science, 309, 1844-1846. Doi: 10.1126/science.1116448. Were K.O., Dick O.B., Singh B.R., 2013. Remotely sensing the spatial and temporal land cover changes in Eastern Mau forest reserve and Lake Nakuru drainage Basin, Kenya. Applied Geography, 41, 75-86. Williams G.A., Helmuth B., Russel B.D., Dong W.-Y., Thiyagarajan V., Seuront L., 2016. Meeting the climate change challenge: Pressing issues in southern China an SE Asian coastal ecosystems. Regional Studies in Marine Science, 8, 373-381. Doi: 10.1016/j.rsma.2016.07.002. Woodroffe C.D., Rogers K., McKee K.L., Lovdelock C.E., Mendelssohn I.A., Saintilan N., 2016. Mangrove sedimentation and response to relative sea-level rise. Annual Review of Marine Science, 8, 243-266. Doi: 10.1146/annurev-marine-122414-034025.

Financial information is one of the important information in decision making. However, many cases of fraud committed by management so that the information in the financial statements cannot be relied upon in decision making. Therefore, the auditor's job is to ensure that the company's financial statements are represented correctly (faithful representation) so that financial statement information becomes more quality and useful in making decisions. So this study aims to examine the effect of audit fee on audit quality. In addition, this study also examines important determinants of audit costs, namely company size, profitability, audit risk, complexity, and firm size. By using the purposive sampling method, samples of the financial and manufacturing industry in 2010-2017 used are 39 firms per year. This sample is used to examine the effect of audit fee on audit quality and the determinant of audit fee using simple linear regression analysis and multiple linear regression analysis. The result of this research shows that audit fees have a significant positive effect on audit quality. In addition, this study shows that firm size, complexity, and firm size are important determinants that determine audit fee. However, profitability and audit risk have not been proven to explain audit fees. Keywords: Audit Quality, Audit Fee, Firm Size, Profitability, Audit Risk, Complexity, Auditor Size Referencens: Al-Harshani, Meshari O. (2008), The pricing of audit services: Evidence from Kuwait. Managerial Auditing Journal, 23(7), 685–696. Al-Thuneibat, Ali. Abedalqader, Ream Tawfiq Ibrahim Al Issa, & Rana Ahmad Ata Baker, (2011), Do audit tenure and firm size contribute to audit quality? Empirical evidence from Jordan. Managerial Auditing Journal, 26(4), 317–334. Arens, Alvin A., Randal J. Elder,. Mark S. Beasley (2014), Auditing and Assurance Services: An Integrated Approach. United States: Pearson Education, Inc. Association of Certified Fraud Examiners (2018), Report to the Nations: 2018 Global Study on Occupational Fraud and Abuse, United States: ACFE. Bhandari, L. C. (1988), Debt/Equity Ratio and Expected Common Stock Returns : Empirical Evidence. The Journal of Finance, 43(2), 507–528. Bowerman, Bruce L., Richard T. O'Connell, Emily S. Murphree (2017), Business Statistics in Practice, Eighth Edition, New York: McGraw Hill Education. Brealey, Richard A., Myers, Stewart C. (2000), Principles of Corporate Finance, Boston: McGraw Hill Companies, Inc. Carey, P. J. (2008), The Benefits of Services Provided by External Accountants to Small and Medium Sized Enterprises. Carey, P., & Simnett, R. (2006), Audit partner tenure and audit quality. Accounting Review, 81(3), 653–676. Castro, Walther Bottaro de Lima, Ivam Ricardo Peleias, & Glauco Peres da Silva (2015), Determinants of Audit Fees: A Study in the Companies Listed on the BM&FBOVESPA, Brasil. Revista Contabilidade & Finanças, 26(69), 261–273. Chen, C. (2008), Audit Partner Tenure , Audit Firm Tenure , and Discretionary Accruals : Does Long Auditor Tenure Impair Earnings Quality ?, 25(2), 415–445. Cooper, D. R., & Schindler, P. S. (2014), Business Research Methods (Twelfth Edition). New York: McGraw-Hill/Irwin. DeAngelo, L. E. (1981), Auditor size and audit quality. Journal of Accounting and Economics, 3(3), 183–199. Dechow, Patricia. M., Richard. G. Sloan, & Amy P. Sweeney (1995), Detecting Earnings Management. The Accounting Review. DeFond, M., & Zhang, J. (2014), A review of archival auditing research. Journal of Accounting and Economics, 58(2–3), 275–326. Deis, Donald R., & Gary Giroux (1996), The effect of auditor changes on audit fees, audit hours, and audit quality. Journal of Accounting and Public Policy, 15(1), 55–76. Eilifsen, Aasmund, Jr William F Messier, Steven M Glover, Douglas F Prawitt (2014), Auditing & Assurance Services, Third Edition, London: McGraw-Hill. Ettredge, Michael., Elizabeth Emeigh Fuerherm, & Chan Li (2014), Fee pressure and audit quality. Accounting, Organizations and Society, 39(4), 247–263. Ferri, Michael G., & Wesley H. Jones (1979), Determinants of financial structure: a new methodological approach. The Journal of Finance, 34(3), 631–643. Francis, Jere. R. (2011), A Framework For Understanding And Researching Audit Quality. Auditing, 30(2), 125–152. Ghozali, H. Imam (2016), Aplikasi Analisis Multivariete dengan Program IBM SPSS 23, Edisi ke-8, Semarang: Badan Penerbit Universitas Diponegoro. Gitman, Lawrence J., Chad J. Zutter (2012), Principles Of Managerial Finance (Thirteenth). United States: Lawrence J. Gitman. Hoitash, Rani., Ariel Markelevich, & Charles A. Barragato (2007), Auditor fees and audit quality. Managerial Auditing Journal, 22(8), 761–786. Horngren, Charles T., L. Sundem, John A. Elliott (1999), Introduction to Financial Accounting, Seventh Edition, New Jersey: Prentice-Hall,Inc. Ikatan Akuntansi Indonesia (2017), Standar Akuntansi Keuangan (SAK), Jakarta: IAI International Accounting Standard Board (2018), The Conceptual Framework for Financial Reporting 2018. London : IASB. Jan, Chyan Long (2018), An effective financial statements fraud detection model for the sustainable development of financial markets: Evidence from Taiwan. Sustainability (Switzerland), 10(2). Jensen, Michael C., & William H. Meckling (1976), Theory Of The Firm : Managerial Behavior , Agency Costs And Ownership Structure, 3, 305–360. Joshi, P. L., & Hasan AL-bastaki (2000), Determinants of Audit Fees : Evidence from the Companies Listed in Bahrain, 138(November 1999), 129–138. Jubb. (1996), Audit fee determinants: The plural nature of risk. Managerial Auditing Journal, 11(3), 25–40. Kieso, Donald E., Jerry J. Weygandt, & Paul D. Kimmel (2013), Financial Accounting IFRS Edition. United States: John Wiley & Sons, Inc. Kieso, Donald E, Jerry J Weygandt, Terry D Warfield (2018), Intermediate Accounting: IFRS Edition Third Edition, United States: John Willey & Sons, Inc. Kikhia, Hassan Yahia (2014), Determinants of Audit Fees: Evidence from Jordan. Accounting and Finance Research, 4(1), 42–53. Knechel, Robert W., & Ann Vanstraelen (2007), The Relationship between Auditor Tenure and Audit Quality Implied by Going Concern Opinions. AUDITING: A Journal of Practice & Theory, 26(May), 113–131. Knechel, W. Robert, Gopal V. Krishnan, Mikhail Pevzner, Lori B Shefchik, & Uma K. Velury (2013), Audit quality: Insights from the academic literature. Auditing, 32(SUPPL.1), 385–421. Konrath, Larry F. (2002), Auditing A Risk Analysis Approach, Fifth Edition, South Western. Kusharyanti (2013), Analysis of the Factors Determining the Audit Fee. Journal of Economics, Business, and Accountancy | Ventura, 16(1), 147–160. Lennox, C. (1999), Are large auditors more accurate than small auditors? Accounting and Business Research, 29(3), 217–227. Lennox, C. S. (1999) Audit quality and auditor size: An evaluation of reputation and deep pockets hypotheses. Journal of Business Finance and Accounting, 26(7–8), 789–805. Liu, Siheng. (2017), An Empirical Study: Auditors’ Characteristics and Audit Fee. Open Journal of Accounting, 06(02), 52–70. Lobo, Gerald, & Yuping Zhao (2013), Relation between Audit Effort and Financial Report Misstatements: Evidence from Quarterly and Annual Restatements. Journal of International Accounting Research, 90(4), 1395–1435. Manry, David L, Theodore J. Mock, & Jerry L. Turner (2008), Does increased audit partner tenure reduce audit quality? Journal of Accounting, Auditing and Finance, 23(4), 553–572. Mohammed, Nishtiman Hashim, & Abdullah Saeed Barwari (2018), Determinants of Audit Fees : Evidence from UK Alternative Investment Market. Academic Journal of Nawroz University, 7(3), 34–47. Musah, A. (2017), Determinants of Audit fees in a Developing Economy: Evidence from Ghana. International Journal of Academic Research in Business and Social Sciences, 7(11). Newton, Nathan J., Dechun Wang, & Michael S. Wilkins (2013), Does a lack of choice lead to lower quality? evidence from auditor competition and client restatements. Auditing, 32(3), 31–67. Nikkinen, J., & Petri Sahlström (2004), Does Agency Theory Provide a General Framework for Audit Pricing ? International Journal of Auditing, 8, 253–262. Ohidoa, T., & Okun, O. O. (2018), Firms Attributes and Audit Fees in Nigeria Quoted Firms. International Journal of Academic Research in Business and Social Sciences, 8(3), 685–699. Pham, Ngoc Kim, Hung Nguyen Duong, Tin Pham Quang, & Nga Ho Thi Thuy (2017), Audit Firm Size, Audit Fee, Audit Reputation and Audit Quality: The Case of Listed Companies in Vietnam. Asian Journal of Finance & Accounting, 9(1), 429. Rahman, Dr Onaolapo Adekunle Abdul, Ajulo Olajide Benjamin, Onifade Hakeem Olayinka (2017), Effect of Audit Fees on Audit Quality: Evidence from Cement Manufacturing Companies in Nigeria. Effect of Audit Fees on Audit Quality: Evidence from Cement Manufacturing Companies in Nigeria., 5(1), 6–17. Rahmina, Listya Yuniastuti, & Sukrisno Agoes (2015), Influence of Auditor Independence, Audit Tenure, and Audit Fee on Audit Quality of Members of Capital Market Accountant Forum in Indonesia. Procedia - Social and Behavioral Sciences, 164(August), 324–331. Republik Indonesia (2008), Undang-Undang Republik Indonesia Nomor 20 tahun 2008 Tentang Usaha Mikro, Kecil, Dan Menengah. Sandra, & Patrick. (1996), The Deteminants of Audit Fees in HongKong: An Empirical Study. Asian Review of Accounting, 4(2), 32–50. Scott, William R (2015), Financial Accounting Theory, Seventh Edition, United States: Pearson Canada Inc. Shibano, T. (1990), Assessing Audit Risk from Errors and Irregularities. Journal of Accounting Research, 28(1990), 110. Sivathaasan, N., R. Tharanika, M. Sinthuja, V. Hanitha (2013), Factors determining Profitability: A Study of Selected Manufacturing Companies listed on Colombo Stock Exchange in Sri Lanka. European Journal of Business and Management, 5(27), 99-107–107. Subramanyam, K. R. (2014), Financial Statement Analysis, Eleventh Edition, New York: McGraw-Hill Education. Sun, Jerry, & Guoping Liu (2011), Client-specific litigation risk and audit quality differentiation. Managerial Auditing Journal, 26(4), 300–316. Tritschler, Jonas (2013), Audit Quality: Association Between Published Reporting Errors and Audit Firm Characteristics. Vu, Dinh Ha Thu Vu (2012), Determinants of audit fees for Swedish listed non-financial firms in NASDAQ OMX Stockholm. Whittington, Ray & Kurt Pany (2004), Principles of Auditing and Other Assurance Services, New York: McGraw-Hill/Irwin. Williams, David D. (1988), The Potential Determinants of Auditor Change. Journal of Business Finance & Accounting, 15(2), 243–261. Wooten, T. C. (2003), Research About Audit Quality. Wu, Shu-Hsing, Tsung-Che Wu, & Kun-Lin Yang (2017), Fair Value Information, Audit fees and Audit Committee in Taiwan. International Journal of Financial Research, 8(2), 124. Xu, Jiabing (2017), Analysis on the Relationship between Audit Fee Management and Audit Quality in China, 53(ICEM 2017), 530–533.

AbstractRobust sunflowers are a generalization of combinatorial sunflowers that have applications in monotone circuit complexity Rossman (SIAM J. Comput. 43:256–279, 2014), DNF sparsification Gopalan et al. (Comput. Complex. 22:275–310 2013), randomness extractors Li et al. (In: APPROX-RANDOM, LIPIcs 116:51:1–13, 2018), and recent advances on the Erdős-Rado sunflower conjecture Alweiss et al. (In: Proceedings of the 52nd Annual ACM SIGACT Symposium on Theory of Computing, STOC. Association for Computing Machinery, New York, NY, USA, 2020) Lovett et al. (From dnf compression to sunflower theorems via regularity, 2019) Rao (Discrete Anal. 8,2020). The recent breakthrough of Alweiss, Lovett, Wu and Zhang Alweiss et al. (In: Proceedings of the 52nd Annual ACM SIGACT Symposium on Theory of Computing, STOC. Association for Computing Machinery, New York, NY, USA, 2020) gives an improved bound on the maximum size of a w-set system that excludes a robust sunflower. In this paper, we use this result to obtain an $$\exp (n^{1/2-o(1)})$$ exp ( n 1 / 2 - o ( 1 ) ) lower bound on the monotone circuit size of an explicit n-variate monotone function, improving the previous best known $$\exp (n^{1/3-o(1)})$$ exp ( n 1 / 3 - o ( 1 ) ) due to Andreev (Algebra and Logic, 26:1–18, 1987) and Harnik and Raz (In: Proceedings of the Thirty-Second Annual ACM Symposium on Theory of Computing, ACM, New York, 2000). We also show an $$\exp (\varOmega (n))$$ exp ( Ω ( n ) ) lower bound on the monotone arithmetic circuit size of a related polynomial via a very simple proof. Finally, we introduce a notion of robust clique-sunflowers and use this to prove an $$n^{\varOmega (k)}$$ n Ω ( k ) lower bound on the monotone circuit size of the CLIQUE function for all $$k \leqslant n^{1/3-o(1)}$$ k ⩽ n 1 / 3 - o ( 1 ) , strengthening the bound of Alon and Boppana (Combinatorica, 7:1–22, 1987).

A sampling campaign was conducted in Gopalganj district of Bihar for assessing the mass concentration of PM2.5 and PM2.5-10 so as to correlate it with the air quality of the district. Concentration of a dozen of elements namely Cd, Cr, Cu, Mn, Ni, Pb, Zn, Fe, Ca, K, Na and Al were quantified. Sampling was done on nuclear polycabonate filters. For principal component analysis (PCA) of elements and mass concentration data, three main sources were identified as PM2.5 and PM2.5-10 concentration. They are resuspended crustal dust, industrial emissions and vehicles exhaust. The effect of weather conditions was also studied. It was found that pollution in summer was higher than those in winter. The PM2.5/PM2.5-10 ratio in summer was found to be in the range of 0.35 - 0.9 whereas the same ratio in winter was 0.20 - 0.50. The concentration of both types of particles exceeded the permissible WHO limits.

Background: Nonalcoholic fatty liver disease (NAFLD) increases risk for obesity-related insulin resistance and type 2 diabetes. Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH) , the rate-limiting enzyme in glucose oxidation, can reverse obesity-induced NAFLD. Moreover, our lab has observed that treatment with the antianginal drug, ranolazine, augments hepatic PDH activity, leading to a reversal of obesity-induced glucose intolerance and NAFLD in mice. Our aim herein was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycemia requires increases in hepatic PDH activity. Methods: We generated liver-specific PDH deficient (PDHLiver-/-) mice by crossing floxed Pdha1 mice with albumin-Cre (Alb-Cre) mice. PDHLiver-/- and Alb-Cre mice were placed on a high-fat diet for 12-weeks to induce obesity, whereas their lean controls were fed a low-fat diet. Mice were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage for 5-weeks, following which we assessed glucose homeostasis and hepatic steatosis. Results: Lean PDHLiver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) from their Alb-Cre littermates, though a mild but nonsignificant worsening of pyruvate tolerance was observed. Similar findings were observed in obese PDHLiver-/- mice compared to their Alb-Cre littermates. Of interest, ranolazine treatment produced mild improvements in glucose tolerance in obese Alb-Cre mice, but not in obese PDHLiver-/- mice. However, this improvement in ranolazine treated Alb-Cre mice appears to be independent of decreases in hepatic triacylglycerol content. Conclusions: Although hepatic PDH activity appears to contribute to the glucose-lowering actions of ranolazine, this appears to be dissociated from its actions on hepatic steatosis, and impaired hepatic PDH activity per se is not sufficient to produce an NAFLD phenotype. Disclosure C. T. Saed: None. S. Tabatabaei dakhili: None. A. A. Greenwell: None. J. S. F. Chan: None. K. Yang: None. K. Gopal: None. F. Eaton: None. J. R. Ussher: None.

Purpose: Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D) , it remains difficult to manage, hence, new therapeutic options are required. We previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone (KB) oxidation, contributes to obesity-induced hyperglycemia. Moreover, we identified that the antipsychotic agent, pimozide, is a SCOT inhibitor with glucose-lowering actions. In silico molecular modeling determined that a wide range of DPBPs can theoretically inhibit SCOT activity, therefore, we determined whether the DPBP drug class could be repurposed for the treatment of T2D. Methods: 8-week-old male wild-type and muscle-specific/brain-specific SCOT knockout (SCOTMuscleKO, SCOTBrainKO) mice were subjected to experimental obesity via consumption of a high fat, high sugar diet for 12-weeks. Lean control mice received a low fat, low sugar diet. At 8-weeks, lean and obese mice were treated with DPBPs (penfluridol, fluspirilene, pimozide (10mg/kg)) once every 2 days via oral gavage for 14-days, following which circulating KB levels and glucose homeostasis were assessed. To rule out a contribution of the canonical actions of DPBPs as dopamine 2 (D2) receptor antagonists to DPBP-mediated glucose-lowering, obese mice were treated with the structurally unrelated D2 receptor antagonist, lurasidone (10 mg/kg) . Results: All tested DPBPs improved glucose homeostasis in obese mice through a mechanism dependent on the inhibition of both brain and muscle SCOT activity. Treatment with lurasidone failed to improve glycemia in obese mice, thus consistent with a SCOT-dependent mechanism of action. Conclusions: Our findings suggest all DPBPs have glucose-lowering actions and therefore may have clinical utility in being repurposed for the treatment of T2D. Disclosure S. Tabatabaei dakhili: None. C. A. Velazquez: None. P. A. Crawford: Advisory Panel; Abbott Diabetes, Johnson & Johnson Global Services. M. Glover: None. R. Al batran: None. J. R. Ussher: None. R. Abou farraj: None. A. A. Greenwell: None. C. T. Saed: None. K. Yang: None. K. Gopal: None. J. S. F. Chan: None. C. Lee: None. F. Eaton: None. Funding Canadian Institutes of HealthResearch

Diabetic cardiomyopathy (DbCM) increases mortality and morbidity in type 2 diabetes (T2D) subjects. Increased cardiac aldose reductase (AR) activity has been correlated with impaired cardiac function and less effective energy metabolism in DbCM subjects. The aim of the present study was to evaluate the effect AT-001, a potent and selective AR inhibitor, on cardiac function, structure, and energy metabolism in diabetic cardiomyopathic mice that overexpress the human AR (hAR-Tg) . The effects of AT-001 were compared to those of dapagliflozin, a sodium-glucose cotransporter inhibitor that decreases the risk of cardiovascular death. DbCM was induced in human AR overexpressing transgenic (hAR-Tg) mice by subjecting them to a high-fat diet (60% kcal from lard) for 10-wk with a single intraperitoneal streptozotocin injection (75 mg/kg) at 4-wk. Male mice were randomized to receive either vehicle, AT-001 (40 mg/kg/day) ,or dapagliflozin (1 mg/kg/day) for the final 3-wk. AT-001 treatment improved diastolic function in vivo (a decrease in the E/e’ ratio and an increase in the E’/A’) and reduced left ventricular mass (LV) mass in DbCM mice compared to vehicle-treated DbCM mice. Cardioprotection by AT-001 was associated with reduced cardiac AR activity, decreased circulating blood sorbitol levels, and a reduction in cardiac fatty acid oxidation rates in the DbCM mice. Treatment with dapagliflozin did not significantly affect either diastolic function or LV mass in DbCM mice. In addition, dapagliflozin did not have a significant effect on cardiac fatty acid oxidation rates. In summary, the present study demonstrates that AT-001 attenuates diastolic dysfunction and cardiac hypertrophy in DbCM. AT-001-induced cardioprotection is accompanied by reduced cardiac fatty oxidation rates in DbCM. Disclosure Q. G. Karwi: None. R. Ramasamy: Consultant; Applied Therapeutics. J. R. Ussher: None. G. Lopaschuk: None. K. Gopal: None. S. Tabatabaei dakhili: None. C. S. Wagg: None. L. Zhang: None. Q. Sun: None. C. T. Saed: None. S. Panidarapu: None. R. Perfetti: Employee; Applied Therapeutics.

International Conference on Current Trend in Physics and Photonics (ICCTPP-2022), a virtual conference was organized by School of Physics, Dr. Vishwanath Karad MIT World Peace University- Pune, India in association with IOP Science Publishing from 9th June to 11th June 2022. The conference was Chaired by Dr. Sachin Kulkarni, Head, School of Physics, MITWPU Pune and Co-Chaired by Prof. Dr. Narendra Mathakari and Dr. Ajit Deore from School of Physics. The purpose of the conference was to bring together leading academic scientists, researchers, industry professionals to exchange and share their experiences and research results on all aspects of general Physics and in particular the emerging field of photonics. In General Physics, the focus was mainly on material science, nanoscience, computational physics and theoretical physics. In Photonics, the focus was primarily on Lasers, Nanophotonics, Green photonics, Solar Energy, Plasmonics and Nonlinear Optics. The three-day conference program was carefully structured to encourage mutual inspiration and fruitful debate among researchers. Well known experts across India and the world were associated with the conference for keynote addresses, plenary sessions and invited talks. In addition, high quality research was presented by academicians, industry professionals, and research scholars from leading institutions across India, UAE, South Korea, Republic of Korea, Thailand, Tunisia and Algeria through oral and poster sessions. Total Ten oral and poster sessions was scheduled with topics ranging from Photonics, Optics, Nano Science and Material Science. On the first day the conference lamp was ignited with the Keynote address of Prof. Jagadish Chennupati, Distinguished Professor and Head of Semiconductor Optoelectronics and Nanotechnology Group in the Research School of Physics, Australian National University, Australia and the Plenary Talk of Prof. Venu Gopal Achanta, Director of CSIR-National Physical Laboratory, India. Prof. Chennupati enlighten the attendees on ‘Semiconductor Nanostructures for Optoelectronics Applications’ and Prof. Achanta on ‘Nanophotonics’. During afternoon session Dr. Nayana Vaval, Scientist, NCL, Pune, India delivered her talk on ‘Study of temporary bound states’ and Dr. Almantas Pivrikas, Senior Lecturer, Murdoch University, Australia expressed his views on ‘opto-electronic devices, such as photovoltaic cells, light emitting diodes, field-effect transistors and sensors’. The second day started with the Plenary talk of Prof. Prashant Sonar, ARC Future Fellow and Professor in School of Chemistry and Physics and Centre for Material Science at Queensland University of Technology, (QUT), Australia on the topic ‘Novel Conjugated Functional Materials for Photonics, Electronics, and Sensing’. Afternoon session was two invited talks, one by Dr. K. V. Sreekanth, Scientist-II, IMRE, A-Star, Singapore on ‘Reconfigurable nanophotonics with chalcogenide phase change materials’ and another by Dr. Dmitry Vasilyev, Dept of Physics, Johannes Gutenberg-Universität Mainz, Germany on ‘Imaging Spin Detection in Microscopy and Spectroscopy’. List of ICCTPP-2022, Committee Members are available in this Pdf.

Abstract Background Observational studies have demonstrated associations between maternal gestational vitamin D status and offspring bone health. We have recently shown, in a randomised controlled trial, that pregnancy vitamin D supplementation leads to improved offspring bone mass at birth amongst winter deliveries (when background 25(OH)-vitamin D levels are lowest). In the present analysis, we aimed to evaluate whether the beneficial effect of pregnancy vitamin D supplementation on neonatal bone mass is sustained into early childhood, with bone indices assessed at age 4 years in a subset of participants of the MAVIDOS trial. Methods Pregnant women were randomised in Southampton, Oxford and Sheffield, in a double-blind design, to 1000 IU/day cholecalciferol or matched placebo from 14 weeks’ gestation to birth. At 4 years of age (Southampton participants only, n = 723 births), offspring assessments included anthropometry, whole-body dual-energy x-ray absorptiometry (DXA) [Hologic Horizon, yielding whole body less head (WBLH) bone mineral content (BMC), bone mineral density (BMD), bone area (BA) and lean mass (LM)], and a maternal questionnaire. Linear regression was used to estimate the mean difference (represented by β) in outcomes between the two randomisation arms, adjusted for sex and age at DXA. Further models were additionally adjusted for gestational age, maternal BMI, and child’s sedentary time. All outcomes were standardised to a standard deviation scale, for ease of comparison. Full ethics and MHRA approvals were granted. Results 564 children attended the 4-year visit; 452 had a useable DXA with minimal movement artefact. Maternal pregnancy vitamin D supplementation led to greater offspring indices of bone mass compared with placebo, irrespective of season. For example, WBLH BMD at age 4 years was greater in the offspring of supplemented mothers [β = 0.18 SD (95%CI: 0.00, 0.35), p = 0.047]; there was also evidence of greater LM in the intervention group [β = 0.15 SD (95%CI: -0.02, 0.31), p = 0.081]. In fully adjusted models associations were consistent for lumbar spine indices and for BA and BMC. In keeping with the offspring findings, maternal vitamin D supplementation led to significantly higher maternal plasma 25(OH)D concentrations in late pregnancy (34 weeks’ gestation): placebo group (median(IQR)): 42.4 nmol/l (23.3, 56.4); vitamin D group: 67.4 nmol/l (56.2, 80.3); p &lt; 0.001. Conclusion This is the first ever demonstration in a large placebo-controlled, double-blind randomised controlled trial that maternal pregnancy vitamin D supplementation leads to improved bone and lean mass in children. Our findings suggest that maternal cholecalciferol supplementation may have lasting benefits for offspring musculoskeletal health and thus represent an important public health message. This work was supported by grants from Versus Arthritis 17702, Medical Research Council (MRC #405050259; #U105960371), Bupa Foundation, NIHR Southampton Biomedical Research Centre (BRC), University of Southampton, and NIHR Oxford BRC, University of Oxford. EC was supported by the Wellcome Trust (#201268/Z/16/Z). Disclosures E.M. Curtis None. R.J. Moon None. S. D'Angelo None. S.R. Crozier None. N.J. Bishop None. S. Gopal- Kothandapani None. S. Kennedy None. A.T. Papageorghiou None. R. Fraser None. S.V. Gandhi None. I. Schoenmakers None. A. Prentice None. H.M. Inskip None. K.M. Godfrey None. K. Javaid None. R. Eastell None. C. Cooper None. N.C. Harvey None.

Abstract Background/Aims Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). About 14-33% of LN patients fail to respond to standard treatment. In this study we evaluated the treatment outcomes of LN patients who failed to respond to standard first-line immunosuppressives and attempted to define the clinical characteristics of ‘difficult-to-treat’ (DTT) LN. Methods Records of all SLE patients from the lupus clinic in our center who underwent renal biopsy were reviewed. Those with class III, IV, and V LN were included. Demographic, clinical, laboratory and histopathological features were recorded. Any patient with inadequate response to first-line induction which, according to the ACR, is disease worsening at three months or treatment failure by six months or who did not have partial or complete response as per EULAR/ERA-EDTA definition, were classified as DTT LN. Those who achieved complete response but developed flares within 24 months of therapy warranting second induction were also considered DTT. All of these patients received a second induction therapy. The outcome of interest was a composite outcome of worsening creatinine, end-stage renal disease (ESRD) or death. Secondary outcomes included response rates, time to achieve response, progression to ESRD, mortality, and adverse events. Results We identified 181 SLE patients (91.7% female) with biopsy-proven LN with complete records who had at least 2-year follow-up from 2004 to 2022. Their age (median, IQR) was 29 (24-32) years, median duration of disease 48 (24-84) months, median SLEDAI-2K was 12 (8-16). Among the initial kidney biopsies, 71 (39.2%) were class III, 74 (40.8%) class IV, 23 (12.7%) pure class V and 13 (7.1%) class III/IV + V. Fifty-seven of 181 (31.4%) were identified as DTT. Among these, 28/57 (49.1%) received second induction treatment, 22/57 (38.6%) received three induction, and 7/57 (12.3%) received &gt;3 induction. Being of male sex, presence of constitutional symptoms, serositis, hypertension, leucopenia, active sediments in the initial urinalysis, anti-Ro-60, anti-U1RNP, any antiphospholipid antibodies (aPLs), low C3, wire loop lesions, interstitial inflammation, fibrinoid necrosis, cellular or fibrocellular crescents, and glomerulosclerosis were significantly associated with DTT LN (Table 1). On multivariate logistic regression, only the presence of aPLs and active urinary sediments remained as independent predictors of DTT LN(table 1). A Kaplan-Meier plot showed the cumulative incidence of the composite outcome to be significantly high in the DTT group. After follow up of 250 months, 24/57 (42.1%) DTT patients were in complete remission and 11/57 (19.3%) in partial remission, while 22/57 (38.6%) remained non-responsive to treatment. Conclusion The burden of DTT LN was 30% in our cohort, of whom 65% responded completely to second or third inductions, while a significant proportion failed to achieve remission even with repeat induction. Presence of active sediments at initial diagnosis and co-existence of aPLs were independent predictors of DTT LN. Disclosure J.B. K l: None. A. Jose: None. V. G: None. B. Mashetty: None. G. M s: None. M. Gorijavolu: None. C. Kavadichanda: None. A. Gopal: None. C. Mariaselvam: None. M.M. Thabah: None. V.S. Negi: None.

The incidence of type 2 diabetes mellitus is rapidly increasing, with many complications pressured on the health care system. Complications of diabetes due to chronic hyperglycemia related to other metabolic disorders, causing damage to the microvascular system. Among them, damaged kidney vessels lead to impair the renal function as diabetic nephropathy is the most common cause of end-stage renal disease. Measurement of glomerular filtration rate (GFR) is an important parameter in assessing renal function. In Vietnam’s hospital, serum creatinine is the biomarker mostly used to assess GFR. However, this biomarker is affected many factors such as gender, age, ... Many studies showed that serum Cystatin C is another biomarker that can detect early decline in GFR, less affected by other factors. Therefore, we conducted this study to explore serum cystatin C and creatinine levels in patients with type 2 diabetes and initially compare GFR in applying formulas of CKD.EPI 2012 and age and sex factors with these two biomarkers on those patient groups. The prospective, descriptive, cross-sectional study was performed on 50 patients with type 2 diabetes. Serum Cystatin C, serum creatinine test was performed and GFR was estimated by CKD.EPI 2012 equation. The results showed that the average serum Cystatin C level of the study group was 0.87 ± 0.24 mg/L that expressed no difference between two genders, and significant difference between age groups. Whereas, the average serum creatinine level of the study group was 81.30 ± 19.70 µmol/L, significant difference between male and female but not difference between age groups. In patients with GFR <60 mL/min/1.73m2, serum creatinine and cystatin C levels were higher than normal but there was no difference with the upper limit in the normal reference range of the two indications. Keyword Type 2 diabetes, serum cystatin C, serum creatinine, glomerular filtration rate. References [1] N.H. Cho, J. Kirigia, J.C. Mnanya, K. Ogurstova, L. Gủaiguata, W. Rathmann, G. Roglic, N. Forouhi, R. Dajani, A. Esteghmati, E. Boyko, L. Hambleton, O.L.M. Neto, P.A. Montoya, S. Joshi, J. Chan, J. Shaw, T.A. Samuels, M. Pavkov, A. Reja, IDF Diabetes Atlas eight edition, International Diabete Federation, 2017. http://fmdiabetes.org/wp-content/uploads/2018/03/IDF-2017.pdf (access 15 july 2019).[2] G. Xu, B. Liu, Y. Sun, Y. Du, L.G. Snetselaar, F.B. Hu, W. Bao, Prevalence of diagnosed type 1 and type 2 diabetes among US adults in 2016 and 2017: population based study, British Medical Journal 361 (2018) k1497. https://doi.org/ 10.1136/bmj.k1497.[3] N.T.T. Minh, N.K. Luong, N.K. Son, The clinical and subclinical characteristics in patients with diabetes mellitus treated at Thai Nguyen General hospital, Journal of pratical medicine 787 (2011) 25-8.[4] N.T.H. Lan, L.D. Tuan, Survey characteristics of renal complication in elderly type 2 diabetes outpatients treated at National Hospital of Endocrinology, Journal of Military Pharmaco-medicine 6 2017 55-62. [5] Mohsen Pourghasem, Hamid Shafi, Zahra, Histological changes of kidney in diabetic nephropathy, Caspian J Intern Med 6(3) (2015) 120-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650785/pdf/cjim-6-120.pdf (access 16 july 2019).[6] D.W. Powell, D.N. Kenagy, S. Zheng, S.C. Coventry, J. Xu, L. Cai, E.C. Carlson, P.N. Epstein, Associations between Structural and Functional Changes to the Kidney in Diabetic Humans and Mice, Life Sci 93(7) (2013) 257-64. https://doi.org/ 10.1016/j.lfs.2013.06.016.[7] Natalie Ebert, Elke Schaeffner, New biomarkers for estimating glomerular filtration rate, Journal of Laboratory and Precision Medicine 3(75) (2018. https://doi.org/10.21037/jlpm.2018.08.07.[8] L.A. Inker, C.H. Schmid, H. Tighiouart, J.H. Eckfeldt, H.I. Feldman, T. Greene, J.W. Kusek, J. Manzi, F.V. Lente, Y.L. Zhang, J. Coresh, A.S. Levey, Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C, The new England Journal of Medicine 367 (2012) 20-9. https://doi.org/ 10.1056/NEJMoa1114248.[9] Ashwin Kumar, Anil Kumar, Serum cystatin C and serum creatinine levels in type 2 diabetes mellitus, International Journal of Research in Medical Sciences 3(1) (2015) 174-7. https://doi.org/10.5455/2320-6012.ijrms20150130.[10] X. Jianguo, D.I. Broadhurst, M. Wilson, D.S. Wishart, Translational biomarker discovery in clinical metabolomics:an introductory tutorial, Metabolomics 9 (2013) 280–99. https://doi.org/ 10.1007/s11306-012-0482-9.[11] B.T. Anh, Estimate the glomerular filtration rate by plasma creatinine and cystatin C concentration, Journal of Vietnam Medicine 2 (2012) 12-18.[12] S. Kakde, S. Alexander, V.G. David, S. Jacob, A. Mohapatra, A.T. Valson, B. Gopal, C.K. Jacob, J. Hephzibah, V. Tamilarasi, S. Varughese, Relationship of creatinine and cystatin C-based estimated glomerular filtration rates with measured glomerular filtration rate in healthy kidney donors from South Asia, Indian J Nephrol 28 (2018) 345-50. https://doi.org/ 0.4103/ijn.IJN 249_17[13] Olympus life science research europa GmbH, Olympus clinical chemistry reagent guide, Olympus Diagnostic, American, 2009.[14] International Society of Nephrology, KDIGO 2012 clinical practice guideline for the evaluation and Management of chronic kidney disease, Kidney Int, Kidney International Supplements 3(1) (2012) 5-14. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf (access 19 july 2019).[15] American Diabete Association, Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes 2018. Diabetes Care, (41(Supplement 1)) (2018) S13-S27. https://diabetesed.net/wp-content/uploads/2017/12/2018-ADA-Standards-of-Care.pdf (access 18 july 2019).[16] L.S. Weinert, A.B. Prates, F.B. do Amaral, M.Z. Vaccoro, J.L. Camargo, S.P. Silveiro, Gender does not influence cystatin C concentrations in healthy volunteers, Clin Chem Lab Med 48(3) (2010) 405-8. https://doi.org/10.1515/CCLM.2010.068.[17] N.T. Ly, T.T.C. Mai, Serum cystatin C and renal function in type 2 diabetic patients, Journal of medical Research 80(3B) (2012) 17-O.Al.[18] Musaimia, A.H. Abu-Nawwas, D.Al. Shaera, N.Y.Khaleela, M.Fawzi, Influence of age, gender, smoking, diabetes, thyroid and cardiac dysfunctions on cystatin C biomarker, Medicina de Familia Semergen 45(1) (2019) 44-51. https://doi.org/ 10.1016/j.semerg.2018.07.005.[19] M.C. Odden, I.B. Tager, R.T. Gansevoort, S.J.L. Bakker, R. Katz, L.F. Fried, et al, Age and cystatin C in healthy adults: a collaborative study, Nephrol Dial Transplant 25(2) (2010) 463-9. https://doi.org/10.1093/ndt/gfp474.[20] E.D. O’ Sullivan, J. Hughes, D.A. Ferenbach, Renal Aging: Causes and Consequences, J Am Soc Nephrol 28 (2017) 407–20. https://doi.org/10.1681/ASN.2015121308.[21] E.D. O’ Sullivan, J. Hughes, D.A. Ferenbach, Renal Aging: Causes and Consequences, J Am Soc Nephrol 28 (2017) 407–20. https://doi.org/10.1681/ASN.2015121308.[22] Christiane Oddoze, Henri Portugal, Yvon Berland, Bertrand Dussol, Cystatin C Is Not More Sensitive Than Creatinine for Detecting Early Renal Impairment in Patients With Diabetes. American Journal of Kidney Diseases, 38(2 (August)), (2001) 310-6. https://doi.org/ 10.1053/ajkd.2001.26096.

Follicular lymphoma (FL) is the most common type of indolent lymphoma in the Western world, accounting for approximately 30% of lymphoma cases. FL is known for its recurrent nature, necessitating diverse treatment options. The introduction of rituximab, an anti-CD20 antibody, has greatly improved FL outcomes and paved the way for targeted therapies. In this review, we thoroughly explore the structure, mechanism of action, clinical outcomes, and side effects of currently approved monoclonal antibodies (mAb) for FL. Furthermore, we provide insights into ongoing clinical trials and emerging monoclonal antibodies that hold promise for the future of FL treatment. A comprehensive literature search was conducted using various medical databases, including ASH and ASCO publications, as well as PubMed. The clinicaltrials.gov website was used to compile a list of investigational monoclonal antibodies from ongoing clinical trials. The future of antibody-based therapy for follicular lymphoma shows great promise, with a focus on enhancing antibody efficacy, prioritizing optimized combination therapies to address treatment resistance, and evaluating bispecific antibodies as first-line therapies, all while carefully balancing risks and benefits and sequencing treatments appropriately for better disease management. These directions have the potential to establish antibodies as a central component of follicular lymphoma treatment. Article Details How to Cite MOUSTAFA, Muhamad Alhaj. A Comprehensive Review of Monoclonal Antibodies for the Treatment of Follicular Lymphoma Including Both Approved and Investigational Options. Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4745>. Date accessed: 02 dec. 2023. doi: https://doi.org/10.18103/mra.v11i11.4745. ABNT APA BibTeX CBE EndNote - EndNote format (Macintosh & Windows) MLA ProCite - RIS format (Macintosh & Windows) RefWorks Reference Manager - RIS format (Windows only) Turabian Issue Vol 11 No 11 (2023): November Issue, Vol.11, Issue 11 Section Research Articles The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives. References 1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569 2. Cerhan JR. Epidemiology of Follicular Lymphoma. Hematol Oncol Clin North Am. 2020;34(4):631-646. doi:10.1016/j.hoc.2020.02.001 3. Kaseb H, Ali MA, Koshy NV. Follicular Lymphoma. In: StatPearls. StatPearls Publishing; 2023. Accessed April 8, 2023. http://www.ncbi.nlm.nih.gov/books/NBK538206/ 4. Monga N, Nastoupil L, Garside J, et al. Burden of illness of follicular lymphoma and marginal zone lymphoma. Ann Hematol. 2019;98(1):175-183. doi:10.1007/s00277-018-3501-8 5. Mozas P, Sorigué M, López-Guillermo A. Follicular lymphoma: an update on diagnosis, prognosis, and management. Med Clin (Barc). 2021;157(9):440-448. doi:10.1016/j.medcli.2021.03.041 6. Luminari S, Bellei M, Biasoli I, Federico M. Follicular lymphoma - treatment and prognostic factors. Rev Bras Hematol E Hemoter. 2012;34(1):54-59. doi:10.5581/1516-8484.20120015 7. Illidge T, Chan C. How have outcomes for patients with follicular lymphoma changed with the addition of monoclonal antibodies? Leuk Lymphoma. 2008;49(7):1263-1273. doi:10.1080/10428190802090805 8. Steffanoni S, Ghielmini M, Moccia A. Chemotherapy and treatment algorithms for follicular lymphoma: a look at all options. Expert Rev Anticancer Ther. 2015;15(11):1337-1349. doi:10.1586/14737140.2015.1092386 9. Flowers CR, Leonard JP, Nastoupil LJ. Novel immunotherapy approaches to follicular lymphoma. Hematol Am Soc Hematol Educ Program. 2018;2018(1):194-199. doi:10.1182/asheducation-2018.1.194 10. Marofi F, Rahman HS, Achmad MH, et al. A Deep Insight Into CAR-T Cell Therapy in Non-Hodgkin Lymphoma: Application, Opportunities, and Future Directions. Front Immunol. 2021;12:681984. doi:10.3389/fimmu.2021.681984 11. Bhatt VR, Armitage JO. Autologous and allogeneic hematopoietic stem cell transplantation in follicular lymphoma. Expert Opin Biol Ther. 2016;16(1):57-66. doi:10.1517/14712598.2016.1096341 12. Lin Z, Liu L, Li Z, Xu B. Bispecific antibodies as monotherapy or in combinations for non-hodgkin B-cell lymphoma: latest updates from the American society of hematology 2022 annual meeting. Exp Hematol Oncol. 2023;12(1):41. doi:10.1186/s40164-023-00404-3 13. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040-2045. doi:10.1182/blood-2010-03-276246 14. van Meerten T, Hagenbeek A. Novel antibodies against follicular non-Hodgkin’s lymphoma. Best Pract Res Clin Haematol. 2011;24(2):231-256. doi:10.1016/j.beha.2011.03.002 15. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med. 2017;377(14):1331-1344. doi:10.1056/NEJMoa1614598 16. Johnston PB, Bondly C, Micallef INM. Ibritumomab tiuxetan for non-Hodgkin’s lymphoma. Expert Rev Anticancer Ther. 2006;6(6):861-869. doi:10.1586/14737140.6.6.861 17. Gondran C, Ysebaert L. [Drug approval: Mosunetuzumab - third-line therapy in follicular lymphoma]. Bull Cancer (Paris). 2022;109(11):1105-1106. doi:10.1016/j.bulcan.2022.07.010 18. Allen HC, Sharma P. Histology, Plasma Cells. In: StatPearls. StatPearls Publishing; 2023. Accessed April 11, 2023. http://www.ncbi.nlm.nih.gov/books/NBK556082/ 19. Nelson PN, Reynolds GM, Waldron EE, Ward E, Giannopoulos K, Murray PG. Monoclonal antibodies. Mol Pathol MP. 2000;53(3):111-117. doi:10.1136/mp.53.3.111 20. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495-497. doi:10.1038/256495a0 21. Dunn DL. Monoclonal antibodies for diagnosis and treatment. Arch Surg Chic Ill 1960. 1993;128(11):1274-1280. doi:10.1001/archsurg.1993.01420230102016 22. Posner J, Barrington P, Brier T, Datta-Mannan A. Monoclonal Antibodies: Past, Present and Future. Handb Exp Pharmacol. 2019;260:81-141. doi:10.1007/164_2019_323 23. Di Pauli F, Berger T, Reindl M. Monoclonal antibodies in the treatment of multiple sclerosis. Curr Med Chem. 2009;16(36):4858-4868. doi:10.2174/092986709789909585 24. Lloyd EC, Gandhi TN, Petty LA. Monoclonal Antibodies for COVID-19. JAMA. 2021;325(10):1015. doi:10.1001/jama.2021.1225 25. Kaur N, Goyal A, Sindhu RK. Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer. Anticancer Agents Med Chem. 2020;20(16):1895-1907. doi:10.2174/1871520620666200703191653 26. Yamada T. Therapeutic monoclonal antibodies. Keio J Med. 2011;60(2):37-46. doi:10.2302/kjm.60.37 27. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435-445. 28. Cerny T, Borisch B, Introna M, Johnson P, Rose AL. Mechanism of action of rituximab: Anticancer Drugs. 2002;13:S3-S10. doi:10.1097/00001813-200211002-00002 29. Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res. 2001;61(13):5137-5144. 30. Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95(12):3900-3908. 31. Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol. 2022;97(12):1638-1651. doi:10.1002/ajh.26737 32. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(15):1986-1992. doi:10.1200/JCO.2006.06.4618 33. Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005;106(12):3725-3732. doi:10.1182/blood-2005-01-0016 34. Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105(4):1417-1423. doi:10.1182/blood-2004-08-3175 35. Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(28):4579-4586. doi:10.1200/JCO.2007.13.5376 36. Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008;112(13):4824-4831. doi:10.1182/blood-2008-04-153189 37. Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97(1):101-106. doi:10.1182/blood.v97.1.101 38. Ghielmini M, Schmitz SFH, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004;103(12):4416-4423. doi:10.1182/blood-2003-10-3411 39. Witzig TE, Vukov AM, Habermann TM, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin’s lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(6):1103-1108. doi:10.1200/JCO.2005.12.052 40. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet Lond Engl. 2011;377(9759):42-51. doi:10.1016/S0140-6736(10)62175-7 41. Martinelli G, Schmitz SFH, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(29):4480-4484. doi:10.1200/JCO.2010.28.4786 42. Hanif N, Anwer F. Rituximab. In: StatPearls. StatPearls Publishing; 2023. Accessed April 15, 2023. http://www.ncbi.nlm.nih.gov/books/NBK564374/ 43. Freeman CL, Sehn LH. A tale of two antibodies: obinutuzumab versus rituximab. Br J Haematol. 2018;182(1):29-45. doi:10.1111/bjh.15232 44. Goede V, Klein C, Stilgenbauer S. Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-hodgkin’s lymphomas: a glycoengineered type II CD20 antibody. Oncol Res Treat. 2015;38(4):185-192. doi:10.1159/000381524 45. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115(22):4393-4402. doi:10.1182/blood-2009-06-225979 46. Niederfellner G, Lammens A, Mundigl O, et al. Epitope characterization and crystal structure of GA101 provide insights into the molecular basis for type I/II distinction of CD20 antibodies. Blood. 2011;118(2):358-367. doi:10.1182/blood-2010-09-305847 47. Suresh T, Lee LX, Joshi J, Barta SK. New antibody approaches to lymphoma therapy. J Hematol OncolJ Hematol Oncol. 2014;7:58. doi:10.1186/s13045-014-0058-4 48. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013;122(7):1137-1143. doi:10.1182/blood-2013-01-481341 49. Amitai I, Gafter-Gvili A, Shargian-Alon L, Raanani P, Gurion R. Obinutuzumab-related adverse events: A systematic review and meta-analysis. Hematol Oncol. 2021;39(2):215-221. doi:10.1002/hon.2828 50. Riley MB. Ibritumomab tiuxetan. Clin J Oncol Nurs. 2003;7(1):110-112. doi:10.1188/03.CJON.109-112 51. Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(16):1977-1983. doi:10.1200/JCO.2012.45.6400 52. Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(15):3262-3269. doi:10.1200/JCO.2002.11.017 53. Rieger K, De Filippi R, Lindén O, et al. 90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years. Ann Hematol. 2022;101(4):781-788. doi:10.1007/s00277-022-04781-3 54. Alhaj Moustafa M, Borah BJ, Moriarty JP, et al. Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas. Clin Lymphoma Myeloma Leuk. 2023;23(4):259-265. doi:10.1016/j.clml.2023.01.010 55. Salvaris R, Ong J, Gregory GP. Bispecific Antibodies: A Review of Development, Clinical Efficacy and Toxicity in B-Cell Lymphomas. J Pers Med. 2021;11(5):355. doi:10.3390/jpm11050355 56. Budde LE, Sehn LH, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022;23(8):1055-1065. doi:10.1016/S1470-2045(22)00335-7 57. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X 58. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1):56. doi:10.1186/s40425-018-0343-9 59. Grigor EJM, Fergusson D, Kekre N, et al. Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta-Analysis. Transfus Med Rev. 2019;33(2):98-110. doi:10.1016/j.tmrv.2019.01.005 60. Nitschke L. The role of CD22 and other inhibitory co-receptors in B-cell activation. Curr Opin Immunol. 2005;17(3):290-297. doi:10.1016/j.coi.2005.03.005 61. Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther. 2021;219:107709. doi:10.1016/j.pharmthera.2020.107709 62. Dakappagari N, Ho SN, Gascoyne RD, Ranuio J, Weng AP, Tangri S. CD80 (B7.1) is expressed on both malignant B cells and nonmalignant stromal cells in non-Hodgkin lymphoma. Cytometry B Clin Cytom. 2012;82(2):112-119. doi:10.1002/cyto.b.20631 63. Deeks ED. Polatuzumab Vedotin: First Global Approval. Drugs. 2019;79(13):1467-1475. doi:10.1007/s40265-019-01175-0 64. Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742. 65. Rosenbaum CA, Jung SH, Pitcher B, et al. Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance). Br J Haematol. 2019;185(1):53-64. doi:10.1111/bjh.15768 66. Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008;111(12):5486-5495. doi:10.1182/blood-2007-10-117671 67. Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012;119(16):3698-3704. doi:10.1182/blood-2011-09-378323 68. Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(20):3346-3353. doi:10.1200/JCO.2008.19.9117 69. Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol Off J Eur Soc Med Oncol. 2010;21(9):1870-1876. doi:10.1093/annonc/mdq027 70. Tobinai K, Ogura M, Kobayashi Y, et al. Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci. 2011;102(2):432-438. doi:10.1111/j.1349-7006.2010.01809.x 71. Ganjoo KN, de Vos S, Pohlman BL, et al. Phase 1/2 study of ocaratuzumab, an Fc-engineered humanized anti-CD20 monoclonal antibody, in low-affinity FcγRIIIa patients with previously treated follicular lymphoma. Leuk Lymphoma. 2015;56(1):42-48. doi:10.3109/10428194.2014.911859 72. Leonard JP, Coleman M, Ketas JC, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(16):3051-3059. doi:10.1200/JCO.2003.01.082 73. Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(12):2085-2093. doi:10.1200/JCO.2009.25.1900 74. Ogura M, Tobinai K, Hatake K, et al. Phase I study of inotuzumab ozogamicin (CMC-544) in Japanese patients with follicular lymphoma pretreated with rituximab-based therapy. Cancer Sci. 2010;101(8):1840-1845. doi:10.1111/j.1349-7006.2010.01601.x 75. Kebriaei P, Cutler C, de Lima M, et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplant. 2018;53(4):449-456. doi:10.1038/s41409-017-0019-y 76. Hamadani M, Radford J, Carlo-Stella C, et al. Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma. Blood. 2021;137(19):2634-2645. doi:10.1182/blood.2020007512 77. Salles G, Gopal AK, Minnema MC, et al. Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma. Clin Lymphoma Myeloma Leuk. 2019;19(5):275-284. doi:10.1016/j.clml.2018.12.013 78. Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol. 2014;164(2):258-265. doi:10.1111/bjh.12630 79. Czuczman MS, Thall A, Witzig TE, et al. Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(19):4390-4398. doi:10.1200/JCO.2005.09.018 80. Armand P, Janssens A, Gritti G, et al. Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma. Blood. 2021;137(5):637-645. doi:10.1182/blood.2019004753 81. Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24(25):4143-4149. doi:10.1200/JCO.2006.05.8198 82. Leonard JP, Coleman M, Kostakoglu L, et al. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(24):5696-5704. doi:10.1200/JCO.2005.14.803 83. Press OW, Unger JM, Rimsza LM, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(3):314-320. doi:10.1200/JCO.2012.42.4101 84. Nastoupil LJ, Chin CK, Westin JR, et al. Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma. Blood Adv. 2022;6(4):1143-1151. doi:10.1182/bloodadvances.2021006240 85. Leonard JP, Schuster SJ, Emmanouilides C, et al. Durable complete responses from therapy with combined epratuzumab and rituximab: final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma. Cancer. 2008;113(10):2714-2723. doi:10.1002/cncr.23890 86. Grant BW, Jung SH, Johnson JL, et al. A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer. 2013;119(21):3797-3804. doi:10.1002/cncr.28299 87. Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019;6(5):e254-e265. doi:10.1016/S2352-3026(19)30026-2 88. Diefenbach C, Kahl BS, McMillan A, et al. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Lancet Haematol. 2021;8(12):e891-e901. doi:10.1016/S2352-3026(21)00311-2 89. Hutchings M, Mous R, Clausen MR, et al. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet Lond Engl. 2021;398(10306):1157-1169. doi:10.1016/S0140-6736(21)00889-8 90. Bannerji R, Arnason JE, Advani RH, et al. Odronextamab, a human CD20×CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022;9(5):e327-e339. doi:10.1016/S2352-3026(22)00072-2 91. Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175 92. Subklewe M. BiTEs better than CAR T cells. Blood Adv. 2021;5(2):607-612. doi:10.1182/bloodadvances.2020001792 93. Tapia-Galisteo A, Compte M, Álvarez-Vallina L, Sanz L. When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy. Theranostics. 2023;13(3):1028-1041. doi:10.7150/thno.81494 94. Wu L, Seung E, Xu L, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nat Cancer. 2020;1(1):86-98. doi:10.1038/s43018-019-0004-z 95. Yao Y, Hu Y, Wang F. Trispecific antibodies for cancer immunotherapy. Immunology. 2023;169(4):389-399. doi:10.1111/imm.13636 96. Fayad L, Offner F, Smith MR, et al. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(5):573-583. doi:10.1200/JCO.2012.42.7211 97. Kolstad A, Illidge T, Bolstad N, et al. Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Adv. 2020;4(17):4091-4101. doi:10.1182/bloodadvances.2020002583 98. Palomba ML, Till BG, Park SI, et al. Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study. Clin Lymphoma Myeloma Leuk. 2022;22(7):e443-e451. doi:10.1016/j.clml.2021.12.010 99. Morschhauser F, Ghosh N, Lossos IS, et al. Obinutuzumab-atezolizumab-lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma: final analysis of a Phase Ib/II trial. Blood Cancer J. 2021;11(8):147. doi:10.1038/s41408-021-00539-8 100. Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012;157(4):438-445. doi:10.1111/j.1365-2141.2012.09086.x 101. Westin JR, Chu F, Zhang M, et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 2014;15(1):69-77. doi:10.1016/S1470-2045(13)70551-5 102. Czuczman MS, Leonard JP, Jung S, et al. Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol Off J Eur Soc Med Oncol. 2012;23(9):2356-2362. doi:10.1093/annonc/mdr620