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The Facility for Rare Isotope Beams (FRIB) began operation with 1 kW beam power for scientific users in May 2022 upon completion of 8 years of project construction. The ramp-up to the ultimate beam power of 400 kW, planned over a 6-year period, will enable the facility to reach its full potential for scientific discovery in isotope science and applications. In December 2023, a record-high beam power of 10.4 kW uranium was delivered to the target. Technological developments and accelerator improvements are being made over the entire facility and are key to completion of the power ramp-up. Major technological developments entail the phased deployment of high-power beam-intercepting systems, including the charge strippers, the charge selection systems, the production target, and the beam dump, along with support systems, including non-conventional utilities (NCU) and remote handling facilities. Major accelerator improvements include renovations to aging legacy systems associated with experimental beam lines and system automation for improved operational efficiency and better machine availability. Experience must be gained to safely handle the increased radiological impacts associated with high beam power; extensive machine studies and advanced beam tuning procedures are needed to minimize uncontrolled beam losses for the desired operating conditions. This paper discusses the technological developments and accelerator improvements with emphasis on major R&D efforts.

Rui Han,1,2 Xiwu Rao,3 Huiling Zhou,4 Lingeng Lu5– 7 1Department of Chinese Medicine Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China; 2Department of Chinese Medicine, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Oncology, The First Hospital Affiliated to Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 4Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of China; 5Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA; 6School of Medicine, Center for Biomedical Data Science, Yale University, New Haven, CT, USA; 7Yale Cancer Center, Yale University, New Haven, CT, USACorrespondence: Rui Han, Department of Chinese Medicine Oncology, The First Affiliated Hospital of Naval Medical University, Shanghai, 200433, People’s Republic of China, Email dianxiqiao@foxmail.comAbstract: The utilization of PD-1/PD-L1 inhibitors marks a significant advancement in cancer therapy. However, the efficacy of monotherapy is still disappointing in a substantial subset of patients, necessitating the exploration of combinational strategies. Emerging from the promising results of the KEYNOTE-942 trial, RNA-based therapies, particularly circRNAs and piRNAs, have distinguished themselves as innovative sensitizers to immune checkpoint inhibitors (ICIs). These non-coding RNAs, notable for their stability and specificity, were once underrecognized but are now known for their crucial roles in regulating PD-L1 expression and bolstering anti-cancer immunity. Our manuscript offers a comprehensive analysis of selected circRNAs and piRNAs, elucidating their immunomodulatory effects and mechanisms, thus underscoring their potential as ICIs enhancers. In conjunction with the recent Nobel Prize-awarded advancements in mRNA vaccine technology, our review highlights the transformative implications of these findings for cancer treatment. We also discuss the prospects of circRNAs and piRNAs in future therapeutic applications and research. This study pioneers the synergistic application of circRNAs and piRNAs as novel sensitizers to augment PD-1/PD-L1 inhibition therapy, demonstrating their unique roles in regulating PD-L1 expression and modulating immune responses. Our findings offer a groundbreaking approach for enhancing the efficacy of cancer immunotherapy, opening new avenues for treatment strategies. This abstract aims to encapsulate the essence of our research and the burgeoning role of these non-coding RNAs in enhancing PD-1/PD-L1 inhibition therapy, encouraging further investigation into this promising field.Keywords: CircRNA, piwi-RNA, immunotherapy, PD-1/PD-L1 blockade, immunotherapy sensitizer, combination therapy

Mengyang Li,1,* Yuting Wang,2,* He Liu,2 Xiaonan Huang,2 Huagang Peng,2 Yi Yang,2 Zhen Hu,2 Jianxiong Dou,2 Chuan Xiao,2 Juan Chen,3 Weilong Shang,2 Xiancai Rao1,2 1Department of Microbiology, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China; 2Department of Microbiology, College of Basic Medical Sciences, Army Medical University, Key Laboratory of Microbial Engineering Under the Educational Committee in Chongqing, Chongqing, 400038, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiancai Rao; Weilong Shang, Department of Microbiology, College of Basic Medical Sciences, Army Medical University, Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing, Chongqing, 400038, People’s Republic of China, Email raoxiancai@126.com; shangwl0414@163.comIntroduction: Nanosized outer membrane vesicles (OMVs) from Gram-negative bacteria have attracted increasing interest because of their antitumor activity. However, the antitumor effects of MVs isolated from Gram-positive bacteria have rarely been investigated.Methods: MVs of Staphylococcus aureus USA300 were prepared and their antitumor efficacy was evaluated using tumor-bearing mouse models. A gene knock-in assay was performed to generate luciferase Antares2–MVs for bioluminescent detection. Cell counting kit-8 and lactic dehydrogenase release assays were used to detect the toxicity of the MVs against tumor cells in vitro. Active caspase-1 and gasdermin D (GSDMD) levels were determined using Western blot, and the tumor inhibition ability of MVs was determined in B16F10 cells treated with a caspase-1 inhibitor.Results: The vesicular particles of S. aureus USA300 MVs were 55.23 ± 8.17 nm in diameter, and 5 μg of MVs remarkably inhibited the growth of B16F10 melanoma in C57BL/6 mice and CT26 colon adenocarcinoma in BALB/c mice. The bioluminescent signals correlated well with the concentrations of the engineered Antares2–MVs (R2 = 0.999), and the sensitivity for bioluminescence imaging was 4 × 10− 3 μg. Antares2–MVs can directly target tumor tissues in vivo, and 20 μg/mL Antares2–MVs considerably reduced the growth of B16F10 and CT26 tumor cells, but not non-carcinomatous bEnd.3 cells. MV treatment substantially increased the level of active caspase-1, which processes GSDMD to trigger pyroptosis in tumor cells. Blocking caspase-1 activation with VX-765 significantly protected tumor cells from MV killing in vitro and in vivo.Conclusion: S. aureus MVs can kill tumor cells by activating the pyroptosis pathway, and the induction of pyroptosis in tumor cells is a promising strategy for cancer treatment. Keywords: Staphylococcus aureus, membrane vesicles, Antares2, cancer therapy, pyroptosis, caspase-1, GSDMD

Shuai Jiang,1,2 Man Xiong,3 Xinyi Rao,3 Jieting Liang,3 Xinghan Zhu,3 Hang Fu,1,2 Jiangyun Chen,3 Chengzeng Wang1,2 1The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Institute for Hospital Management of Henan Province, Zhengzhou, Henan, People’s Republic of China; 3School of Health Management, Southern Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Chengzeng Wang; Jiangyun Chen, Email chengzengw@163.com; cjy112@i.smu.edu.cnPurpose: This study aims to investigate factors affecting medical personnel behavioral preferences for providing mHealth in China, so as to provide decision-making basis for mHealth providers and managers to encourage more doctors to participate in mHealth service delivery.Methods: Typical case sampling techniques were applied in a hospital setting to conduct a discrete choice experimental questionnaire survey of doctors (n=216) concerning mHealth preferences between July and October 2022. A conditional logit model was used to assess medical personnel preferences for each attribute and level of mHealth services.Results: Length of service, information security, subjects of treatment and financial compensation all have a significant effect on medical staff’s preference for providing mHealth services (p < 0.05). In terms of service duration and financial compensation, medical staff preferred mHealth services that provided shorter service duration and higher financial compensation; in terms of information security, medical staff preferred mHealth services with confidentiality of diagnostic and therapeutic information compared to information disclosure; and in terms of treatment targets, medical staff preferred the general population compared to key populations, such as pregnant women, the elderly, infants and children.Conclusion: The preference of medical professionals to provide mHealth services is affected by a variety of factors. By enhancing the confidentiality of information in mHealth services, providing more options for service recipients, increasing their financial compensation, and shortening the duration of the service or increasing the number of service hours that can be adjusted can guide improvement of mHealth services and promoting of its adoption among medical professionals.Keywords: doctor, mHealth, preferences, discrete choice experiment

The superconducting ECR source magnet for the Facility for Rare Isotope Beams at Michigan State University was designed and built by the Superconducting Magnet Group at Lawrence Berkeley National Laboratory (LBNL). The 28-GHz NbTi ion source magnet features a sextupole-in-solenoids configuration, which is comparable to the VENUS ECR magnet operated at LBNL. A shell-based support structure using bladders and keys has been incorporated into the design to allow for adjustments of the preload and reversibility of the magnet assembly process. The magnet has been assembled and successfully tested to operational currents at LBNL. This paper describes the basic design of the magnet and the passive quench protection system. The test results are also presented, including the quench behavior of the magnet, the training performance, and the magnetic measurement results.

The superconducting electron cyclotron resonance (ECR) source magnet for the facility for rare isotope beams at Michigan State University was designed and built by the Superconducting Magnet Group at Lawrence Berkeley National Laboratory (LBNL) in 2017. The 28 GHz NbTi ion source magnet features a sextupole-in-solenoids configuration which is comparable to the VENUS ECR magnet operated at LBNL. However, the mechanical design of this magnet utilizes a shell-based support structure which allows fine adjustments to the sextupole preload and reversibility of the magnet assembly process. The magnet has been assembled and tested to operational currents at LBNL. This paper describes the mechanical analyses performed to estimate the sextupole's and solenoids' preloads. We will report on the 3-D finite element analysis during room temperature assembly, cool-down, and magnet excitation, and then describe the magnet preload operations. Finally, we will describe the performance of the support structure during the quench training.

Chuan Guo,1,2 Yarong Wang,1 Yuanlin Piao,1 Xiangrong Rao,2 Dehai Yin1 1Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, People’s Republic of China; 2Department of Nephropathy, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, People’s Republic of ChinaCorrespondence: Dehai YinDepartment of Traditional Chinese Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, No. 1 Shuaifuyuan, Beijing 100730, People’s Republic of ChinaEmail yindehai123@126.comBackground: Diabetic nephropathy (DN) is a common form of diabetic complication which threatens the health of patients with diabetes. It has been reported that chrysophanol (CHR) can alleviate the progression of diabetes; however, the role of CHR in DN remains unclear.Methods: To mimic DN in vitro, human podocytes (AB8/13 cells) were treated with high glucose (HG). Meanwhile, Western blot was performed to detect protein expressions. CCK-8 assay was used to test cell viability and cell proliferation was detected by Ki-67 staining. In addition, flow cytometry was performed to investigate cell apoptosis and cycle and cell migration was tested by transwell assay. Moreover, in vivo model of DN was established to detect the effect of CHR on DN in vivo.Results: HG-induced AB8/13 cell growth inhibition was significantly rescued by CHR. In addition, HG notably promoted the migration of AB8/13 cells, while this phenomenon was obviously reversed by CHR. Moreover, CHR inhibited the progression of DN via inactivation of TGF-β/EMT axis. Furthermore, CHR alleviated the symptom of DN in vivo.Conclusion: CHR significantly alleviated the progression of DN via inactivation of TGF-β/EMT signaling in vitro and in vivo. Our findings were helpful to uncover the mechanism by which CHR regulates DN, as well as inspire the development of novel therapy against DN.Keywords: diabetic nephropathy, chrysophanol, TGF-β, EMT

Haiyang Wang,1,2,* Lanxiang Liu,1,3,* Xuechen Rao,1,2,* Tingjia Chai,1,* Benhua Zeng,4 Xiaotong Zhang,1 Ying Yu,1 Chanjuan Zhou,1 Juncai Pu,1,3 Wei Zhou,1 Wenxia Li,4 Hanping Zhang,1,3 Hong Wei,4 Peng Xie1–3 1NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 2College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 4Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng XieNHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing 400016, People’s Republic of ChinaTel +86-23-68485490Email xiepeng@cqmu.edu.cnHong WeiDepartment of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, People’s Republic of ChinaTel +86-23-68752051Email weihong63528@163.comIntroduction: Recently, an increasing number of studies have focused on commensal microbiota. These microorganisms have been suggested to impact human health and disease. However, only a small amount of data exists to support the assessment of the influences that commensal microbiota exert on olfactory function.Methods: We used a buried food pellet test (BFPT) to investigate and compare olfactory functions in adult, male, germ-free (GF) and specific-pathogen-free (SPF) mice, then examined and compared the metabolomic profiles for olfactory bulbs (OBs) isolated from GF and SPF mice to uncover the mechanisms associated with olfactory dysfunction.Results: We found that the absence of commensal microbiota was able to influence olfactory function and the metabolic signatures of OBs, with 38 metabolites presenting significant differences between the two groups. These metabolites were primarily associated with disturbances in glycolysis, the tricarboxylic acid (TCA) cycle, amino acid metabolism, and purine catabolism. Finally, the commensal microbiota regulation of metabolic networks during olfactory dysfunction was identified, based on an integrated analysis of metabolite, protein, and mRNA levels.Conclusion: This study demonstrated that the absence of commensal microbiota may impair olfactory function and disrupt metabolic networks. These findings provide a new entry-point for understanding olfactory-associated disorders and their potential underlying mechanisms.Keywords: gut microbiota, germ-free, olfactory bulb, metabolomic, gas chromatography-mass spectrometry

The Superconducting Magnet Program at the Lawrence Berkeley National Laboratory (LBNL) is completing the design of a 28 GHz NbTi ion source magnet for the Facility for Rare Isotope Beams (FRIB). The design parameters are based on the parameters of the ECR ion source VENUS in operation at LBNL since 2002 featuring a sextupole-in-solenoids configuration. Whereas most of the magnet components (such as conductor, magnetic design, protection scheme) remain very similar to the VENUS magnet components, the support structure of the FRIB ion source uses a different concept. A shell-based support structure using bladders and keys is implemented in the design allowing fine tuning of the sextupole preload and reversibility of the magnet assembly process. As part of the design work, conductor insulation scheme, coil fabrication processes and assembly procedures are also explored to optimize performance. We present the main features of the design emphasizing the integrated design approach used at LBNL to achieve this result.

Combination of RT and αPD-1 can result in enhanced efficacy in both local and systemic (abscopal) tumor control, relying on CD8+ T cells. However, many patients do not respond. Fenofibrate (FF) is a PPARα agonist, approved for the management of hypercholesterolemia and hypertriglyceridemia. It has also shown antitumoral effects in preclinical investigations. Our study explores the potential synergistic impact of a triple combination comprising RT, αPD-1, and FF in augmenting both local and systemic tumor control in an abscopal tumor model. Mice harboring bilateral B16-CD133 melanoma tumors were treated with 8 Gy x 3 to the primary tumor. αPD-1 was administered weekly, and FF was administered daily on weekdays for several weeks. Tumor sizes and mouse survival were determined. Tumor-specific CD8+ T cells and tumor-associated high endothelial venules (TA-HEVs) were quantified through flow cytometry (FACS). The therapeutic efficacy of the triple combination markedly surpassed that of all double combinations (n≥6 mice/group, p<0.05). Moreover, when CD8+ T cells were depleted with anti-CD8 antibodies, tumor control and survival were not different in triple-treated mice vs. mice treated with the respective double combinations, demonstrating that the triple combination effects depended on CD8+ T cells. In line with this, we found increased numbers of tumor-specific CD8+ T cells in both primary and secondary tumor of triple-treated mice (n≥5 mice/group: p<0.05 compared to all respective double-treated groups). Furthermore, the triple combination group showed an increase in TA-HEVs (n≥5 mice/group: p<0.05 compared to all respective double-treated groups). Adding FF to hRT+ αPD-1 substantially enhanced control of both primary, irradiated and secondary, non-irradiated tumor depending on CD8+ T cells and correlating with an increase in TA-HEVs, pivotal sites facilitating lymphocyte entry into tumors. We are currently performing further mechanistic experiments to better understand the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, this effect is still clinically rare and improvements are highly desirable. We here compared two triple therapy regimens (RT+⍺PD1+⍺CTLA4 vs. RT+⍺PD1+IL2/⍺IL2 complexes [IL2c]) for their efficacy to improve systemic (abscopal) anti-tumor effects. In mice bearing bilateral subcutaneous C51 colon carcinoma, the primary tumor was irradiated with two fractions of 8 Gy. ⍺PD1 and ⍺CTLA4 were given concomitantly and weekly thereafter; IL2c was given i.p. for 3 consecutive days. Besides tumor size and survival, tumor-specific CD8+ T cells were determined flow cytometrically using MHC-I tetramers and various antibodies. In addition, isolated TILs were cultured with PMA, ionomycin, and Brefeldin A in vitro to assess polyfunctionality (based on cytokine production) of CD8+ and CD4+ TILs. The abscopal effect was significantly stronger in mice treated with the ⍺CTLA4-containing triple combination (n = 13) than in mice treated with the IL2c-containing triple combination (n = 9) (p<0,05), and compared to mice treated with RT+⍺PD1 (n = 8) (p<0,05) or RT+⍺CTLA4 (n = 10) (p<0,05), respectively. The IL2c triple combination induced the abscopal effect better than RT+⍺PD1 (p<0,05). The ⍺CTLA4 triple therapy improved survival and resulted in complete cures of 8/13 mice. In mice treated with ⍺CTLA4-containing triple therapy, control of the irradiated tumor was partially dependent and that of the non-irradiated tumor was strongly dependent on T cells, primarily CD8+ T cells but also CD4+ T cells. In mice treated with the IL-2c triple combination, tumor control was more dependent on CD8+ T cells. With ⍺CTLA4 triple treatment (n = 9), the frequency and absolute numbers of polyfunctional TNF-⍺+IFN-g+ tumor-specific CD8+ T cells, TNF-⍺+IFN-g+ CD4+ and IFN-g+IL2+ CD4+ effector T cells were higher than with the IL2c triple combination (n = 9) (p<0,05), particularly in the non-irradiated tumor. We also found that ⍺CTLA-4 triple treatment induced higher CD80+CD86+ expression on dendritic cells than IL-2c triple treatment. hRT+⍺PD1+⍺CTLA4 triple treatment induced more cytotoxic effector TILs than hRT+⍺PD1+IL2c triple treatment, enhancing the abscopal effect and inducing a high abscopal cure rate. [ABSTRACT FROM AUTHOR]