Populations of widespread species are usually geographically distributed through contrasting stresses, but underlying genetic mechanisms controlling this adaptation remain largely unknown. Here, we show that in Arabidopsis thaliana , allelic changes in the cis-regulatory elements, WT box and W box, in the promoter of a key transcription factor associated with oxygen sensing, RELATED TO AP 2.12 (RAP2.12), are responsible for differentially regulating tolerance to drought and flooding. These two cis-elements are regulated by different transcription factors that downstream of RAP2.12 results in differential accumulation of hypoxia-responsive transcripts. The evolution from one cis-element haplotype to the other is associated with the colonization of humid environments from arid habitats. This gene thus promotes both drought and flooding adaptation via an adaptive mechanism that diversifies its regulation through noncoding alleles.

6044 Background: Capecitabine maintenance therapy improves outcomes in various tumor types, but minimal data are available on the effect of capecitabine maintenance therapy in metastatic nasopharyngeal carcinoma (NPC). We aimed to investigate whether capecitabine maintenance therapy would prolong the progression-free survival (PFS) of newly diagnosed metastatic NPC, in comparison to best supportive care (BSC). Methods: This was an open-label, randomized, controlled, phase trial. Eligible patients for maintenance randomisation were aged 18-65 years old with newly diagnosed metastatic NPC at the Sun Yat-Sun University Cancer Center (SYSUCC), had completed 4 to 6 cycles of induction chemotherapy as per protocol and had achieved disease control to protocol treatment, including capecitabine. Patients were randomly assigned 1:1 to capecitabine maintenance (oral 1,250 mg/m²/day on days 1-14 every 21 days) for up to 24 months with BSC or BSC alone. The primary endpoint was PFS. The secondary endpoints included overall survival, duration of response, objective response rate and adverse effects. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02460419 and is ongoing and no longer recruiting new patients. Results: Between May 16th, 2015, and January 9th, 2020, 140 metastatic NPC patients were screened, and 104 eligible patients were randomly assigned to capecitabine maintenance plus BSC (n = 52) or BSC alone (n = 52). After a median follow-up of 33.1 months (IQR, 21.5-50.7 months), median PFS was 35.2 months in the capecitabine maintenance group and 9.1 months in the BSC group (HR: 0.426; 95%CI: 0.248-0.731, P = 0.001). The most commongrade 3 or 4 adverse events during maintenance therapy were hand-foot syndrome (10.0%), nausea/vomiting (6.0%), fatigue (4.0%), and mucositis (4.0%). Totally 37 deaths occurred during follow-up, 14 (26.9%) in the capecitabine maintenance group and 23 (44.2%) in the BSC group. Overall survival data was immature. No deaths in the capecitabine maintenance group were deemed treatment related. Conclusions: Capecitabine maintenance significantly improved PFS in patients with newly diagnosed metastatic NPC who achieved disease control after induction chemotherapy compared to BSC and exhibited low grade and manageable toxicities. Clinical trial information: NCT02460419.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Lu Zhang1, 2, *, Huai Liu4, 5, 6, *, Lin-Quan Tang1, 2, Qiu-Yan Chen1, 2, Shan-Shan Guo1, 2, Li-Ting Liu1, 2, Ling Guo1, 2, Hao-Yuan Mo1, 2, Chong Zhao1, 2, Xiang Guo1, 2, Ka-Jia Cao1, 2, Chao-Nan Qian1, 2, Mu-Sheng Zeng1, Jian-Yong Shao1, 7, Ying Sun1, 8, Jun Ma1, 8, Ming-Huang Hong1, 3, Hai-Qiang Mai1, 2 1Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China 2Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 3GCP center, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 4Department of Radiotherapy, Hunan Cancer Hospital, Changsha, P. R. China 5Department of Radiotherapy, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, P. R. China 6Key Laboratory of Translational Radiation Oncology, Changsha, P. R. China 7Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China 8Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China *These authors contributed equally to this work Correspondence to: Ming-Huang Hong, e-mail: hongmh@sysucc.org.cn Hai-Qiang Mai, e-mail: maihq@sysucc.org.cn Keywords: nasopharyngeal carcinoma, pregnancy, prognosis, survival Received: December 10, 2015 Accepted: February 21, 2016 Published: March 09, 2016

Background Tumor-infiltrating regulatory T (Treg) cells aid the development and progression of tumors by inhibiting the anti-tumor immune response. This immunosuppressive effect often leads to resistance against current immunotherapies for certain cancers .^{1 2} Although the first generation Treg-depleting CTLA-4 antibody ipilimumab has shown clinical efficacy, its use, particularly in combination with PD-1 inhibitors, has been associated with severe immune-related adverse events.³ To address this difficulty, we set out to develop a next-generation Treg-depleting antibody with improved efficacy and safety. Since tumor-infiltrating Treg cells consistently exhibit higher expression levels of both CTLA-4 and OX40 compared to T cells in the periphery across multiple cancer types,^{4 5} we developed an Fc-enhanced CTLA-4×OX40 bispecific IgG1 antibody, YH006, designed to deplete tumor-infiltrating Treg cells with better specificity. YH006 was generated from the RenLite® mouse, which contains a fully human common light chain to facilitate bispecific antibody assembly and the downstream CMC process. Methods The ability of YH006 to promote T-cell responses in vitro was measured by effector cytokine secretion from staphylococcal enterotoxin b-stimulated human PBMCs, and ADCC activity in the context of effector NK-92 cells (with CD16A expression) and human Treg cells, measured by flow cytometry. The in vivo anti-tumor activity of YH006 was evaluated in B-hCTLA-4/hOX40 humanized mice with syngeneic tumors. Transaminase and serum cytokine levels were monitored to determine the preclinical safety of YH006 in vivo. The physiochemical properties of YH006 were assessed by HPLC and LC-MS. Results YH006 treatment and ADCC activity over ipilimumab in vitro. In vivo syngeneic tumor studies demonstrated a superior and dose-dependent anti-tumor activity of YH006 compared to both ipilimumab analog and its Fc-enhanced parental monoclonal antibodies at low doses. Tumor-infiltrating lymphocyte analysis revealed that YH006 treatment can better increase the intra-tumoral CD8/Treg ratio compared with ipilimumab analog. YH006 also showed dose-dependent efficacy in GL261 syngeneic model. Notably, YH006 synergized with PD-1 or PD-L1 antibodies in syngeneic MC38 and B16F10-OVA models. Importantly, YH006 treatment did not elevate liver enzymes or induce production of inflammatory cytokines. Ongoing CMC process development has a titer of 6.9 g/L at the 3L scale, and the purification yield is 80.7%, suggesting excellent quality without homodimers detected. YH006 has consistent quality from research cell bank (RCB) to passage 97. Conclusions YH006 demonstrated superior anti-tumor efficacy across several tumor models and excellent physiochemical properties, which make it a promising candidate for further development as a cancer treatment. References Saleh R, Elkord E. Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 2019;457:168–79. Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci 2019;110(7):2080–89. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017;377(19):1824–35. Montler R, Bell RB, Thalhofer C, et al. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. Clin Transl Immunology 2016;5(4):e70. Arce Vargas F, Furness AJS, Litchfield K, et al. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer Cell 2018;33(4):649–63 e4. Ethics Approval All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Biocytogen Beijing Co., Ltd.