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Human papilloma virus type 16 (HPV16) is the most prevalent etiologic agent associated with cervical cancer, and its early proteins E5, E6 and E7 play important roles in cervical epithelium transformation to cervical intraepithelial neoplasia and even cervical cancer. Hence, these oncoproteins are ideal target antigens for developing immunotherapeutic vaccines against HPV-associated infection and cervical cancer. Currently, multi-epitope vaccines have been a promising strategy for immunotherapy for viral infection or cancers. In this study, the E5aa28-46, E6aa37-57 and E7aa26-57 peptides were selected and linked to form a novel multi-epitopes vaccine (E765m), which was inserted into the major immune dominant region (MIR) of hepatitis B virus core antigen (HBc) to construct a HBc-E765m chimeric virus-like particles (cVLPs). The immunogenicity and immunotherapeutic effect of the cVLPs vaccine was evaluated in immunized mice and a tumor-bearing mouse model. The results showed that HBc-E765m cVLPs elicited high E5-, E6- and E7- specific CTL and serum IgG antibody responses, and also relatively high levels of the cytokines IFN-γ, IL-4 and IL-5. More importantly, the cVLPs vaccine significant suppressed tumor growth in mice bearing E5-TC-1 tumors. Our findings provide strong evidence that this novel HBc-E765m cVLPs vaccine could be a candidate vaccine for specific immunotherapy in HPV16-associated cervical intraepithelial neoplasia or cervical cancer.

Background The HER2 immunohistochemistry (IHC) test is an essential method for detecting breast cancer (BC) and plays a pivotal role in guiding personalized treatment strategies. However, inconsistencies persist among different pathologists using IHC, especially for HER2-low and HER2-negative. This may lead to discrepant clinical decisions, potentially impacting patient outcomes. Since HER2 exists in both dimeric and monomeric forms in cells, certain binding sites of diagnostic antibodies on HER2 dimers may be partially obscured in detection. Therefore, accurately detecting HER2 dimers in IHC is crucial for improving diagnostic precision. Methods We aligned the structures of HER2 heterodimers and Fabs of pertuzumab and trastuzumab binding to HER2, and found they binding in the same region. To overcome the steric hindrance of HER2 dimers, we employed HER2-binding affibody (Aby) and nanobody (Nby) to construct their fusion protein (Nby-Aby) and human heavy chain ferritin (HFn) based nanoparticles (Nby-HFn, Aby-HFn) for detection. Since the Nby and Aby bind HER2 at two distinct regions that are separate from the HER2 dimerization region, effectively minimizing interference from HER2 dimerization in detection. We assessed the detection performance of Nby-Aby in BC tissues and compared it with conventional HER2 diagnostic antibodies using tissue microarrays (TMAs). Results The Nby-Aby assay had higher detection sensitivity for HER2-positive cells in BC tissues compared to the conventional method. Additionally, significantly higher HER2 scores were observed in most BC tissues on tissue microarrays (TMAs) compared to those diagnosed using the traditional method. These findings suggest that dual-targeting and overcoming steric hindrance in HER2 IHC detection is a promising strategy to enhance diagnostic precision. Conclusions Dual-targeting different regions and overcoming steric hindrance of HER2 in IHC detection through the Nby-Aby fusion protein enhances diagnostic sensitivity, providing a novel strategy for more accurate HER2 IHC assessment in BC diagnosis.

The long noncoding RNASBF2-AS1 can promote the occurrence and development of many kinds of tumours, but its role in oesophageal squamous cell carcinoma (ESCC) is unknown. We found that SBF2-AS1 was up-regulated in ESCC, and its expression was positively correlated with tumor size (P = 0.0001), but was not related to gender, age, TNM stage, histological grade, and lymphnode metastasis (P > 0.05). It was further found that the higher the expression of SBF2-AS1, the lower the survival rate. COX multivariate analysis showed that the expression of SBF2-AS1 was an independent prognostic factor. Functional experiments show that inhibition of SBF2-AS1 can inhibit the proliferation of ESCC through in vivo and in vitro, and overexpression of SBF2-AS1 can promote the proliferation of ESCC and inhibit its apoptosis. In mechanism, SBF2-AS1/miR-338-3P, miR-362-3P/E2F1 axis are involved in the regulation of ESCC growth. In general, SBF2-AS1 may be used as ceRNA to combine with miR-338-3P and miR-362-3P to up-regulate the expression ofE2F1, and ultimately play a role in promoting cancer. It may be used as a therapeutic target and a biomarker for prognosis.

Nasopharyngeal carcinoma (NPC) is a tumor of the head and neck, with a higher incidence in southern China and Southeast Asia. Radiotherapy and chemotherapy are the main treatments; however, metastasis and recurrence remain the main causes of treatment failure. Further, the majority of patients are diagnosed in the late stage due to lack of tumor-specific biomarker for early diagnosis. Therefore, an effective treatment and early detection can improve the outcome of patient with NPC. Axl and EGFR are co-expressed in NPC tissues and play key roles in tumor proliferation, migration, and invasion, which are often correlated with poor prognosis and therapy resistance. In this study, we generated a novel bispecific affibody (Z239-1907) for the dual targeting and inhibition of Axl and EGFR expression in NPC-positive cells both in vitro and in vivo. The in vitro experiments demonstrated that Z239-1907 had more pronounced antitumor effects than either modality alone (ZAXL239 or ZEGFR1907) in NPC-positive cells. Further, mice bearing NPC-positive tumors showed significant inhibition in tumor growth after treatment with Z239-1907 compared to ZAXL239 and ZEGFR1907. The in vivo tumor targeting ability and imaging also showed that Z239-1907 specifically and selectively targeted NPC xenograft mice models and accumulate at tumor site as early as 30 min and disappeared within 24 h post-injection. Collectively, these results suggest that Z239-1907 dual-target affibody is a promising therapeutic agent and a molecular imaging probe for early diagnosis in NPC.

Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (Z HPV16E6 1115, Z HPV16E6 1171, and Z HPV16E6 1235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo . Moreover, by binding to HPV16 E6 protein, Z HPV16E6 1235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, Z HPV16E6 1235 was applied in combination with HPV16 E7-binding affibody Z HPV16E7 384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions.

High-risk papillomavirus (HPV) is one of the major reasons for cervical cancer, causing most lethal gynecologic malignancies worldwide. For cervical cancer progression, oncogene E7 plays vital roles and is used as one of the major targets for cervical tumor diagnosis and treatment. In the clinic, successful treatment of cervical cancer relies on diagnosing the disease at an early stage, where a late-stage diagnosis usually led to treatment failure. In this work, we designed and purified an HPV18 E7 oncogene targeting affibody, named as Z HPV18E7 , for in vitro and in vivo imaging and targeted treatment of cervical cancer. In vitro, Z HPV18E7 showed a specific targeting effect against an HPV18 positive cell line; as a contrast, the affibody did not target the HPV18 negative cell line. In vivo, we tested the bio-distribution of the affibody in mice bearing cervical cancer. The whole animal imaging analysis indicated the affibody-targeted tumor tissue specifically with 10 min after injection, and the affibody reached the highest level at tumor tissues 45 min after injection. At the 24th hour after injection, the affibody still maintained a certain level in tumor tissues compared to other organs. To test the therapeutic effect of this affibody, we modified the affibody (i.e., Z HPV18E7 ) with a clinically used anti-cancer agent (i.e., Pseudomonas exotoxin ). In a mice cervical cancer model, Z HPV18E7 was able to deliver Pseudomonas exotoxin to tumor tissues effectively, showing great potential for cancer treatment. This study indicated that Z HPV18E7 could be employed for in vitro imaging and targeted treatment of cervical cancer. Beyond the chemotherapeutic agent used in this work, the affibody could be extended for carrying other therapeutic agents for cervical cancer treatment.

Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) latent infection and is common in Southern China and Southeast Asia. The viral latent membrane proteins LMP1 and LMP2 are persistently expressed in NPC tissues; the cytoplasmic domain of LMP1 (LMP1 C-terminal) and LMP2A (LMP2A N-terminal) proteins is essential for maintenance of latency and can alter host cell signaling to facilitate tumor growth and progression. Thus, targeting LMP1 or LMP2 oncoprotein has been an increasing interest for diagnosis and targeted therapy of NPC. Affibody molecules, a new class of small-affinity engineered scaffold proteins, have demonstrated high potential for therapeutics, diagnostics, and biotechnological applications. More recently, radiolabelled HER2-specific affibody molecules have demonstrated to be useful in imaging of HER2 expressing tumor. In this study, we report three novel EBV LMP1 C-terminal (EBV LMP1-C) domain affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) were selected by biopanning from a random-peptide displayed phage library and used for molecular imaging in tumor-bearing nude mice. Surface plasmon resonance (SPR), indirect immunofluorescence, and immunohistochemistry (IHC) clearly showed that all three selected affibody molecules have high affinity and specificity in binding to EBV LMP1 protein. Moreover, in vivo tumor imaging revealed that Dylight-755-labeled affibody molecules accumulated rapidly in tumor site after injection (1 h) and then were continuously maintained for 24 h in EBV-positive NPC xenograft mice model. In conclusion, our findings highlight the potential use of ZLMP1-C affibody molecules as tumor-specific molecular imaging agents of EBV-associated NPC.Key points• We screened three novel affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) targeting EBV LMP1-C terminal domain• ZLMP1-C recognize the recombinant and native LMP1-C with high affinity and specificity• ZLMP1-C can be used for molecular imaging

针对当前乡村耕地资源闲置浪费与利用率低下等问题，从精准脱贫与乡村振兴有机衔接视角，研究贫困地区耕地流转现状及其驱动机制，为盘活乡村耕地资源、促进区域稳定持续脱贫与乡村振兴提供理论支撑。本文以西北干旱区精准脱贫与乡村振兴示范区盐池县为例，基于93个行政村的问卷调研数据，运用ArcGIS及地理探测器等工具，研究盐池县耕地流转分异特征、主导因素及作用机制。结果表明：盐池县耕地流转存在明显的地域差异性，呈现\"北高南低，中部密集\"的趋势；人均耕地面积、水浇地面积、合作社运营状态、特色产业数量以及到县级干道距离是影响盐池县耕地流转的主导因素，各因素对耕地流转的影响力分别为0.247、0.264、0.028、0.065、0.091。土地利用是驱动盐池县耕地流转的主要因素，未来应加强水利工程建设，增加水浇地面积，加强农业合作社经营与特色产业培育，促进耕地资源流转与可持续利用。

为探究锌/硒互作对小麦和玉米锌和硒累积的影响，本研究通过田间试验，对小麦和玉米进行单独及复合叶面喷施锌肥和硒肥处理，分析不同处理对作物锌硒含量的影响。结果表明：单独喷施锌肥（0.4%硫酸锌）能够提高小麦和玉米籽粒中的锌含量，使其籽粒锌含量分别由36.51 mg·kg-1和37.10 mg·kg-1提升至42.48 mg·kg-1和42.96 mg·kg-1，达到了谷物富锌参考值（40 mg·kg-1）。单独喷施硒肥（0.004%亚硒酸钠或0.004%硒酸钠）显著提高了小麦和玉米籽粒硒含量，且在玉米中硒酸钠的效果优于亚硒酸钠：喷施亚硒酸钠和硒酸钠使小麦籽粒硒含量由0.22 mg·kg-1分别提高至0.69 mg·kg-1和0.74 mg·kg-1；使玉米籽粒硒含量由0.06 mg·kg-1分别提高至0.29 mg·kg-1和0.59 mg·kg-1，均达到谷物富硒参考值（0.15 mg·kg-1）。相对于单独喷施锌肥，锌/硒复合进一步增加了小麦籽粒锌含量，且复配硒酸钠的效果优于复配亚硒酸钠，分别增加16.01%和23.58%。而对于玉米，与单独喷施锌肥相比，锌硒复合对籽粒锌含量略有降低。不同形态硒肥与锌肥复合对作物硒含量产生了不同的影响：相对于单独喷施，亚硒酸钠复合锌后表现为轻微拮抗效果，硒酸盐复合后则表现为进一步提高了小麦和玉米籽粒硒含量，分别高出59.46%和83.05%。研究表明，不同叶面喷施处理均能增加小麦籽粒锌硒含量，硒酸钠复合硫酸锌增加锌、硒效果最好。对于玉米，叶面单独喷施硫酸锌增锌效果最为明显，硒酸盐复合硫酸锌喷施增加的硒含量最高。

为了探究锌肥施用对我国小麦籽粒锌含量的影响，本研究通过文献查阅和数据收集，分析了我国小麦籽粒锌含量特征以及不同锌肥施用方式对小麦籽粒锌含量的影响。结果表明，我国小麦锌肥施用方式主要有土壤施用、叶面喷施以及土壤施用+叶面喷施，且土壤施用时锌的平均投入量（12.6 kg·hm-2）大于叶面喷施（1.57 kg·hm-2）。不施锌肥时小麦籽粒锌含量范围为14.6～50.0 mg·kg-1，且95.3%的小麦籽粒锌含量低于40 mg·kg-1；土壤施用+叶面喷施处理时小麦籽粒锌含量范围为24.0～70.9 mg·kg-1，且76.2%的小麦籽粒锌含量高于40 mg·kg-1。锌肥的施用显著提高了小麦籽粒中的锌含量，不同施肥方式下小麦籽粒锌含量平均增率排序为土壤施用+叶面喷施（62.6%）>叶面喷施（47.2%）>土壤施用（24.6%）。土壤施用或叶面喷施锌肥时，小麦籽粒锌含量增率与外源锌投入量呈显著正相关（P<0.05），当每公顷锌投入量增加1 kg时，籽粒锌含量分别提高0.74%和16.39%。土壤施用、土壤施用+叶面喷施时锌肥的平均利用率较低（0.59%、0.94%），而叶面喷施锌肥平均利用率较高（7.27%）。研究表明，不同施锌方式均能提高小麦籽粒锌含量，且土壤施用+叶面喷施的效果最好，而叶面喷施方式下锌肥利用率最高。