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Abstract Background Preference-based measures of health-related quality of life (HRQoL), such as the EQ-5D or the SF-6D, are essential for health economic evaluation. However, they are rarely included in clinical trials of ankylosing spondylitis (AS). This study aims to develop mapping algorithms to predict EQ-5D-3L and EQ-5D-5L health utility scores from the Bath Ankylosing Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). Methods Patients with AS were recruited from the largest tertiary hospital in Shandong province, China, between December 2019 and October 2020. Patients were selected by convenience sampling method according to the following criteria: (1) diagnosed with AS according to the New York criteria; (2) aged 18 years and above; and (3) without mental disorders; (4) able to understand the questionnaires; (5) without serious complications. There were 243 patients who completed the face-to-face questionnaire survey, and 5 cases with missing values in key variables were excluded. Ordinary least squares, censored least absolute deviations, Tobit, adjusted limited dependent variable mixture model and beta-mixture model (BM) in the direct approach and ordered logit and multinomial logit (Mlogit) model in the response approach were used to develop mapping algorithms. Mean absolute error, root mean square error, Spearman’s correlation coefficient and concordance correlation coefficient were used to access predictive performance. Results The 238 patients with AS had a mean age of 35.19 (SD = 9.59) years, and the majority (74.47%) were male. The observed EQ-5D-3L and EQ-5D-5L health utility values were 0.88 (SD = 0.12) and 0.74 (SD = 0.27), respectively. The EQ-5D-5L had higher conceptual overlap with the BASDAI and BASFI than the EQ-5D-3L did. The Mlogit was the best-performing model for the EQ-5D-3L, and the BM showed better performance in predicting EQ-5D-5L than other direct and indirect mapping models did. Conclusion This study demonstrates that the EQ-5D-5L, rather than EQ-5D-3L, should be selected as the target outcome measure of HRQoL in patients with AS in China, and the BM mapping algorithm could be used to predict EQ-5D-5L values from BASDAI and BASFI for health economic evaluation.

Abstract Background This study aimed to investigate functions of GLP-1R agonist by liraglutide (LIRA) and revealing the mechanism related to AGEs/RAGE in chondrocytes. Methods To illustrate potential effect of GLP-1R agonist on AGEs induced chondrocytes, chondrocytes were administrated by AGEs with LIRA and GLP-1R inhibitor exendin. Inflammatory factors were assessed using ELISA. Real-time PCR was used to evaluate the catabolic activity MMPs and ADAMTS mRNA level, as well as anabolic activity (aggrecan and collagen II). RAGE expression was investigated by Western blotting. TUNEL, caspase3 activity and immunofluorescence were performed to test the apoptotic activity. Results Our results showed that treatment with LIRA at > 100 nM attenuated the AGE-induced chondrocyte viability. Western bolt demonstrated that GLP-1R activation by LIRA treatment reduced RAGE protein expression compared with the AGEs groups. ELISA showed that LIRA hindered the AGEs-induced production of inflammatory cytokines (IL-6, IL-12 and TNF-α) in primary chondrocytes. AGEs induced catabolism levels (MMP-1, -3, -13 and ADAMTS-4, 5) are also attenuated by LIRA, causing the retention of more extracellular matrix (Aggrecan and Collagen II). TUNEL, caspase3 activity and immunofluorescence results indicated that LIRA inhibited the AGEs-induced production of inflammatory cytokines in primary chondrocytes and attenuated the caspase 3 level, leading to the reduced apoptotic activity. All the protective effects are reversed by exendin (GLP-1R blockers). Conclusions The present study demonstrates for the first time that LIRA, an agonist for GLP-1R which is commonly used in type 2 diabetes reverses AGEs induced chondrocyte inflammation and apoptosis through suppressing RAGE signaling, contributing to reduced catabolism and retention of more extracellular matrix. The above results indicate the possible effect of GLP-1R agonist on treating OA.

Abstract Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off‐body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter‐experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms.

Introduction: Lower limb exoskeletons have shown considerable potential in assisting human walking, particularly by reducing metabolic cost (MC), leading to a surge of interest in this field in recent years. However, owing to significant individual differences and the uncertainty of movements, challenges still exist in the personalized design and control of exoskeletons in human-robot interactions.Methods: In this study, we propose a hybrid data-driven approach that integrates musculoskeletal simulation with machine learning technology to customize personalized assistance strategies efficiently and adaptively for ankle-foot exoskeletons. First, optimal assistance strategies that can theoretically minimize MC, were derived from forward muscle-driven simulations on an open-source dataset. Then, a neural network was utilized to explore the relationships among different individuals, movements, and optimal strategies, thus developing a predictive model.Results: With respect to transfer learning, our approach exhibited effectiveness and adaptability when faced with new individuals and movements. The simulation results further indicated that our approach successfully reduced the MC of calf muscles by approximately 20% compared to normal walking conditions.Discussion: This hybrid approach offers an alternative for personalizing assistance strategy that may further guide exoskeleton design.

ObjectiveObservational studies have revealed a link between inflammatory bowel disease (IBD) and sarcopenia. However, it remains unclear whether this correlation between IBD and sarcopenia is causal.MethodsThe genetic instrumental variables (IVs) associated with IBD and sarcopenia-related traits were derived from publicly available genome-wide association studies. We employed a two-sample bidirectional Mendelian randomization (MR) method. we obtained genetic IVs for five phenotypes from 34,652 cases in IBD, 27,432 cases in ulcerative colitis (UC), 212356 cases in crohn’s disease (CD), 9336415 cases in low hand grip strength (LHGS), and 450243 cases in appendicular lean mass (ALM), respectively. The inverse variance weighting and other MR methods were used to explore the bidirectional causal relationship. Furthermore, we performed heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate MR to evaluate the robustness of the results.ResultsThe forward MR results showed that the UC (OR=0.994, 95% CI: 0.9876–0.9998, P = 0.044) and CD (OR=0.993, 95% CI: 0.988–0.998, P = 0.006) was negatively correlated with ALM. In the reverse MR analysis, we also found that LHGS was negatively correlated with the IBD (OR=0.76, 95% CI: 0.61–0.94, P = 0.012) and CD (OR=0.53, 95% CI: 0.40–0.70, P

Abstract In unmanned aerial vehicle (UAV)‐assisted wireless sensor networks (WSNs), UAVs are employed to collect sensing data from each sensor node (SN). Because of limited battery capacity, shortening the time of data collection by the UAV is necessary. Notably, the task completion time is related to UAV trajectory and spectrum allocation. In this paper, joint trajectory design and spectrum allocation is studied to minimize the task completion time of UAVs while ensuring the target upload data amount for each SN. The cases that all SNs are located within the communication range of a UAV is explored first; the formulated problem is non‐convex and difficult to solve directly. Hence, an iterative algorithm based on block coordinate descent and successive convex approximation is proposed to decompose and transformed the original problem into two convex optimizations. Furthermore, the proposed algorithm is applied to the general case that all SNs are widely distributed by leveraging the spiral algorithm and traveling salesman problem technique. Simulation results show that the proposed algorithm can effectively reduce the task time of UAV compared to other benchmark algorithms.

Objective We aimed to provide a comprehensive assessment of health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) of different activities and to evaluate the correlation between clinical activity measures and HRQoL instruments. This research also analysed the extent to which different aspects of HRQoL (physical, psychological and social) were affected.Design Cross-sectional, observational, non-interventional study.Setting The study was conducted at the Department of Rheumatology and Immunology, Qilu Hospital, Shandong University.Methods From December 2019 to October 2020, a total of 340 RA patients participated in the survey using convenient sampling. Three generic instruments, EQ-5D-5L,SF-12 and the AQoL-4D, as well as an RA-specific instrument,the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI), were administered to assess patients’ HRQoL. The Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) was used by doctors to measure patients’ clinical activity. Multivariable linear regression was used to compare patients’ HRQoL across different levels of activity. Spearman’s correlation was used to assess the correlation between doctor-reported clinical activity and HRQoL.Results A total of 314 patients with RA participated in this study. The mean score of HAQ-DI was 0.87 (SD: 0.91). Using patients in the clinical remission group as a reference, patients in the moderate and high disease activity groups showed significantly reduced health state utility values and HRQoL scores (all p

BackgroundLMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies.MethodsA phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets.ResultsThe study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed.DiscussionFurther testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings.Clinical trial registrationhttps://www.clinicaltrials.gov/study/NCT04034238.

We identified Wdr17 as a highly expressed gene in pachytene spermatocytes by transcriptomic analysis of mouse testis. Germ cell-deficient infertile mouse models had significantly reduced Wdr17 expression. We performed gene interference and overexpression in the mouse spermatocyte cell line GC-2spd(ts) and investigated how Wdr17 affects spermatocyte growth and development. Our results showed that Wdr17 suppression significantly decreased cell growth rate and increased cell apoptosis in GC-2spd(ts) cells. Wdr17 suppression also arrested the cell cycle at the G1 phase. On the contrary, Wdr17 overexpression significantly promoted cell proliferation and inhibited cell apoptosis in GC-2spd(ts) cells. More cells were enriched at the S stage with a concomitant reduction of cells at the G1 stage. Wdr17 promotes mouse spermatocyte proliferation by advancing cell cycle progression and inhibiting cell apoptosis, indicating its potential role in regulating spermatogenesis in the mouse.

BackgroundLuminal B and triple-negative breast cancer (TNBC) are malignant subtypes of breast cancer (BC), which can be attributed to the multifaceted roles of tissue-derived exosomes (T-exos). Competing endogenous RNA (ceRNA) networks can regulate gene expression post-transcriptionally.MethodsRNAs in T-exos from luminal B BC (n=8) and TNBC (n=8) patients were compared with those from persons with benign breast disease (n=8). The differentially expressed (DE) mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) target genes were annotated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to reveal the relevant biological processes.The ceRNA networks were constructed to show distinct regulation, and the mRNAs involved were annotated. The miRNAs involved in the ceRNA networks were screened with the Kaplan–Meier Plotter database to identify dysregulated ceRNAs with prognostic power.ResultsIn total, 802 DE mRNAs, 441 DE lncRNAs, and 104 DE miRNAs were identified in luminal B BC T-exos, while 1699 DE mRNAs, 590 DE lncRNAs, and 277 DE miRNAs were identified in TNBC T-exos. Gene annotation revealed that the RAS–MAPK pathway was the primary biological process in luminal B BC T-exos, while endocrine system development and growth were the main processes in TNBC T-exos. Survival analysis established seven survival-related lncRNA/miRNA/mRNA regulations in luminal B BC T-exos, and nineteen survival-related lncRNA/miRNA/mRNA regulations in TNBC T-exos.ConclusionIn addition to survival-related ceRNA regulations, ceRNA regulation of RAS–MAPK in luminal B and endocrine system development and growth regulation in TNBC might contribute to the tumorigenesis of BC.

Background: With the increasing prevalence of obesity and metabolic syndrome, the incidence of non-alcoholic fatty liver disease (NAFLD) is also increasing. In the next decade, NAFLD may become the main cause of liver transplantation. Therefore, the choice of treatment plan is particularly important. The purpose of this study was to compare several interventions in the treatment of NAFLD to provide some reference for clinicians in selecting treatment methods.Methods: We searched Public Medicine (PubMed), Medline, Excerpta Medica Database (Embase), and Cochrane Library from January 2013 to January 2023 to identify randomized controlled trials (RCTs) published in English. The network meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Forty-three studies accounting for a total of 2,969 patients were included, and alanine aminotransferase (ALT), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL) were selected as outcome measures for analysis and comparison.Results: We evaluated the results of drug, diet, and lifestyle interventions between the intervention and control groups. Curcumin (CUN) and probiotics (PTC) were selected for medication, the Mediterranean diet (MDED) was selected for special diet (SPD), and various kinds of exercise and lifestyle advice were selected for lifestyle interventions (LFT). The SUCRA was used to rank interventions according to the effect on ALT indicators (SUCRA: PTC 80.3%, SPD 65.2%, LFT 61.4%, PLB 32.8%, CUN 10.2%), TC indicators (SUCRA: PTC 89.4%, SPD 64%, CUN 34%, LFT 36.6%, PLB 17%), and LDL indicators (SUCRA: PTC 84.2%, CUN 69.5%, LFT 51.7%, PLB 30.1%, SPD 14.5%). The pairwise meta-analysis results showed that MDED was significantly better than NT in improving ALT [SMD 1.99, 95% CI (0.38, 3.60)]. In terms of improving TC and LDL, ATS was significantly better than NT [SMD 0.19, 95% CI (0.03, 0.36)] [SMD 0.18, 95% CI (0.01, 0.35)].Conclusion: Our study showed that PTC is most likely to be the most effective treatment for improving NAFLD indicators. Professional advice on diet or exercise was more effective in treating NAFLD than no intervention.

Abstract Mammography is used to detect breast cancer (BC), but its sensitivity is limited, especially for dense breasts. Circulating cell-free DNA (cfDNA) methylation tests is expected to compensate for the deficiency of mammography. We derived a specific panel of markers based on computational analysis of the DNA methylation profiles from The Cancer Genome Atlas (TCGA). Through training (n = 160) and validation set (n = 69), we developed a diagnostic prediction model with 26 markers, which yielded a sensitivity of 89.37% and a specificity of 100% for differentiating malignant disease from normal lesions [AUROC = 0.9816 (95% CI: 96.09-100%), and AUPRC = 0.9704 (95% CI: 94.54–99.46%)]. A simplified 4-marker model including cg23035715, cg16304215, cg20072171, and cg21501525 had a similar diagnostic power [AUROC = 0.9796 (95% CI: 95.56–100%), and AUPRC = 0.9220 (95% CI: 91.02–94.37%)]. We found that a single cfDNA methylation marker, cg23035715, has a high diagnostic power [AUROC = 0.9395 (95% CI: 89.72–99.27%), and AUPRC = 0.9111 (95% CI: 88.45–93.76%)], with a sensitivity of 84.90% and a specificity of 93.88%. In an independent testing dataset (n = 104), the obtained diagnostic prediction model discriminated BC patients from normal controls with high accuracy [AUROC = 0.9449 (95% CI: 90.07–98.91%), and AUPRC = 0.8640 (95% CI: 82.82–89.98%)]. We compared the diagnostic power of cfDNA methylation and mammography. Our model yielded a sensitivity of 94.79% (95% CI: 78.72–97.87%) and a specificity of 98.70% (95% CI: 86.36–100%) for differentiating malignant disease from normal lesions [AUROC = 0.9815 (95% CI: 96.75–99.55%), and AUPRC = 0.9800 (95% CI: 96.6–99.4%)], with better diagnostic power and had better diagnostic power than that of using mammography [AUROC = 0.9315 (95% CI: 89.95–96.34%), and AUPRC = 0.9490 (95% CI: 91.7–98.1%)]. In addition, hypermethylation profiling provided insights into lymph node metastasis stratifications (p

Abstract Background Mounting evidence in the cancer literature suggests that microRNAs (miRNAs) influence the progression of human cancer cells by targeting protein-coding genes. How insulin-like growth factor 1(IGF1) and miR-186-3p contribute to the development of cervical cancer (CC) remains unclear. This study examined the regulatory roles of miR-186-3p and IGF1 in CC development. Methods Gene expression levels were determined by qRT-PCR. Proliferation, migration, and apoptosis of CC and normal cells were determined by MTT, Transwell, and caspase-3 activity assays, respectively. Dual-luciferase reporter activity and RNA pull-down assays were performed to identify the target gene of miR-186-3p. Results IGF1 was the target of miR-186-3p. The expression of miR-186-3p inhibited cell proliferation and migration abilities of CC cell lines, but induced the apoptosis rate of CC cells. IGF1 could restore the inhibitory effects of miR-186-3p on the proliferation, migration, and apoptosis abilities of CC cells. Experimental results revealed that miR-186-3p could inhibit IGF1 expression, thereby reducing the viability of CC cells. Conclusions The data suggest that targeting of IGF1 by miR-186-3p could be crucial in regulating the progression of CC.

Mesothelin (MSLN) is overexpressed by many cancers, including pancreatic ductal adenocarcinoma (PDAC) and has consequently become a target for anti-cancer therapeutics. Mature, membrane bound MSLN is cleaved by proteases, releasing a shed form that transits to the circulation. Many patients with mesothelioma and ovarian cancer have abnormally high serum MSLN concentration. However, serum MSLN concentration in PDAC patients rarely exceeds levels of healthy controls. Here, serum MSLN concentration in advanced PDAC patients was examined pre- and post-treatment. Serum MSLN did not correlate with tumor MSLN expression, nor with changes in tumor burden as assessed by PDAC serum tumor marker CA19–9. Subsequently, tumor-bearing mouse models were used to investigate the fate of shed MSLN in PDAC versus a control cervical cancer model. Efficiency of MSLN secretion into the serum was cell-line dependent. Tumors from some PDAC lines had poor MSLN secretion efficiency although these lines had similar or higher MSLN shedding rate, total and surface MSLN expression. Measurements of compartment-specific MSLN concentration taken at equilibrium suggested that tumors with poor MSLN secretion efficiency trapped shed MSLN in the tumor microenvironment (TME), a finding confirmed by dynamic experiments using a doxycycline-inducible MSLN expression system. Tumors with the poorest MSLN secretion efficiency had higher collagen density and increased abundance of MSLN binding partner MUC16. The tumor with the worst secretion efficiency could rebind shed MSLN to the cancer cell surface. Altogether, these data suggest that PDAC can trap shed MSLN within the TME. This finding has potential significance for design of MSLN-targeted therapeutics.

Abnormal DNA methylation contributes to breast cancer (BC). Immune-related genes play crucial roles in BC development and progression. This study aims to investigate the effect of methylation of immune-related genes in peripheral blood leukocytes (PBLs) on BC risk. GSE51032 and GSE104942 datasets were used to identify significantly differentially methylated CpG sites (DMCs) of immune-related genes. A case-control study was conducted using MethylTarget sequencing to validate the relationship between the methylation levels of the screened genes and BC risk. We also evaluated the association between methylation haplotypes of screened genes and BC risk. Moreover, we sorted the blood leukocytes into T cells, B cells, and monocytes to detect the difference of DNA methylation in different cell subtypes. A total of five DMCs were screened from GEO datasets, including cg01760846 (PSMC1), cg07141527 (SPPL3), cg15658543 (CARD11), cg21568368 (PSMB8), and cg24045276 (NCF2). In the case-control study, there were significant associations between methylation of the CpG sites in the five genes and BC risk. Methylation haplotype burdens of PSMC1, CARD11, and PSMB8 were associated with reduced BC risk. Moreover, there were heterogeneities in the methylation levels of the genes in different cell subtypes. In conclusion, methylation of PSMC1, SPPL3, CARD11, PSMB8, and NCF2 in PBLs were associated with BC risk. The five-gene methylation could be the potential biomarkers for predicting BC risk.

In this article, the secure communication in cell-free massive multiple-input multiple-output system with low-resolution analog-to-digital converters is investigated in the presence of an active eavesdropper. Specifically, in this article, the deterioration caused by the analog-to-digital converter imperfections on the accuracy of the channel estimation and secure transmission performance is studied. Besides, the additive quantization noise model is utilized to analyze the impacts of the low-resolution analog-to-digital converters. The minimum mean square error channel estimation results show that there is a nonzero floor caused by the coarse analog-to-digital converters. Then, the closed-form expressions for both the legitimate users achievable ergodic rate and the information leakage to the eavesdropper are derived, respectively. Moreover, tight approximated ergodic secrecy rate expression is also presented with respect to analog-to-digital converters quantization bits, number of antennas, pilot power, and so on. To degrade the impacts of the pilot spoofing attack, an active attack detection approach based on random matrix theory is proposed which can only be operated at one access point. Simulation results are provided to corroborate the obtained results and analyze the impacts of various parameters on system secrecy performance. Also, the superiority of the proposed active attacks detection method is confirmed via simulation results.

In any industry, Equipment Asset Management (EAM) is at the core of the production activities. With the rapid development of Industrial Internet technologies and platforms, the EAM based on the Industrial Internet has become an important development trend. Meanwhile, the paradigm of EAM is changing, from a single machine to integrated systems, from the phase of using them to the end of their lifecycle, from breakdown maintenance to predictive maintenance, and from local decision-making to collaborative optimization. However, because of the lack of a unified understanding of the Industrial Internet platforms (IIPs) and the lack of a comprehensive reference architecture and detailed implementation framework, the implementation of EAM projects will face greater risks according to special needs in different industries. Based on the method of system engineering, this study proposes a general reference model and a reference architecture of implementation for the Industrial Internet Solution for Industrial Equipment Asset Management (I3EAM). Further, to help enterprise to evaluate and select their best-fit I3EAM scheme and platform partner, we proposed a set of performance indicators of I3EAM schemes and a quantitative decision-making method based on fuzzy DEMATEL-TOPSIS. Finally, a case study for an I3EAM in automated container terminals was conducted. In the multi-criteria decision environment with complex uncertainty, the project group identified the I3EAM metrics priorities and social digitalization platforms that were more in line with the actual needs of the automated container terminal and firms. The complexity and time of the decision-making process were dramatically reduced. In terms of feasibility and validity, the decision result was positively verified by the feedback from the enterprise implementation. The given model, architecture, and method in this study can create a certain reference value for various industrial enterprises to carry out the analysis and top-level planning of their I3EAM needs and choose the partner for co-implementation. In addition, the research results of this study have the potential to support the construction of standard systems and the planning and optimization of the cross-domain social platform, etc.

This paper investigates the secure transmission in multi-pair massive multiple-input multiple-output amplify-and-forward (AF) relaying networks under active pilot spoofing attacks. The AF relaying beamforming and the artificial noise generation are designed based on the imperfect estimated channel state information. Exploiting a random matrix theory, we first derive the tractable analytical expressions for the end-to-end signal-to-interference-plus-noise ratios (SINRs) at both the intended user and the eavesdropper. Then, we provide the asymptotic results for derived SINRs with respect to the infinite number of relay antennas, unbounded transmit power, and relay power, which show that the SINRs at intended user and eavesdropper are both limited by specific bounds and the effects of relay noise or received additive noise will be eliminated in these extreme power cases. Moreover, power scaling laws are studied to reveal that only the scaled relay power is effective, while source power has no scaling properties for secure transmission in the considered system. To mitigate the severe information leakage, by superimposing a random detection pilot sequence on the training sequence, a simple method based on the minimum description length criterion is provided to detect the presence of the pilot spoofing attacks. The numerical results are provided to confirm the accuracy of our theoretical derivations and illustrate the effectiveness of the proposed scheme.

In this paper, we investigate the secure transmission in multigroup multicasting cell-free massive MIMO system in the presence of pilot spoofing attack. With the imperfect uplink and downlink channel estimation, a distributed conjugate beamforming processing with normalized power constraint policy is exploited at access points (APs) for downlink multicasting data transmission. Closed-form expressions for the per-user achievable rate are derived with and without downlink training, respectively. Also, the analytical results of the upper bound on the information leakage to eavesdropper are carried out. Moreover, a mechanism based on the minimum description length (MDL) is presented to detect pilot spoofing attack. Consequently, the achievable ergodic secrecy rate is obtained to evaluate the system's secrecy performance. The numerical results are presented to quantitatively analyze the impacts of eavesdropper's spoofing pilot power and the number of groups on the secrecy performance of the considered systems.

High-Frequency Pressure Fluctuation (HFPF) is an extensively observed hydraulic phenomenon in pumped-storage power stations and water conveyance projects. The investigation of the propagation characteristics of the pressure perturbation is of great significance for the safe operation of hydraulic facilities. In this study, a one-dimensional (1D)–three-dimensional (3D) coupling model is established based on the combination of the Method of Characteristics (MOC) and Computational Fluid Dynamics (CFD) and implanted in the open source software OpenFOAM. The established model in this study implants the dynamic mesh module into the original OpenFOAM solver sonicLiquidFoam and presents the complete solution procedure of the CFD model with the dynamic mesh considered. The vibration of the pipe walls modeled by the mesh motion is employed to numerically generate the HFPF in the hydraulic system, which could not be implemented in the traditional MOC model. The independence of the pressure perturbation in the pipeline system is validated by the time-domain pressure variation. The graphical method is applied to describe the multiple reflection and superposition characteristics of the traveling wave in a simplified hydraulic system. Based on this, the mechanism of the superimposed characteristic of the traveling and standing pressure waves in the hydraulic system are analyzed, and the theoretical superimposed time-domain processes and the variations of the pressure oscillation magnitude are analyzed and presented. The 1D–3D coupling method and the theoretical analysis method could be referenced by other complex hydraulic systems.

Antibiotic growth promoters have been banned in animal husbandry and aquaculture in China, since 2020. Florfenicol (FLO) is the most used antibiotics in aquaculture for controlling various bacterial disease in fish, although its effect on health of farmed fish remains a concern. In the present study, European seabass (Dicentrarchus labrax) reared under flow-through aquaculture system (FAS) and recirculating aquaculture system (RAS), were fed on diets supplemented with FLO for 10 d, followed by a 20-d withdrawal period. The effects of FLO on the growth performance, intestinal digestive enzyme activities, serum biochemical parameters, antioxidant enzymes, and expression of related genes, were evaluated. The results showed that FLO exposure inhibited growth performance of D. labrax although this was recovered after stopping the feeding. Besides, FLO suppressed α-Amylase and trypsin activities in the intestine, and the amounts of nutrition-related indicators were also affected. In addition, FLO exposure upregulated liver cellular damage markers (ALT, ALP, and AST) during the treatment phase, although it did not pose a high potential for liver damage. We also observed elevated levels of SOD, CAT, and MDA in gills, indicative of oxidative stress on the cultured fish. Moreover, integrated biomarker response results indicated that fish in RAS had higher growth performance and immunity in the late post-treatment phase, relative to those in RAS, after FLO exposure. This was attributed to high-efficient water treatment of RAS. Overall, these results indicate that exposure to FLO modulates digestive enzyme activities and antioxidant response in European seabass, thereby affecting their growth performance and immune response under different aquaculture modes.

Background: Breast ultrasound is the first choice for breast tumor diagnosis in China, but the Breast Imaging Reporting and Data System (BI-RADS) categorization routinely used in the clinic often leads to unnecessary biopsy. Radiologists have no ability to predict molecular subtypes with important pathological information that can guide clinical treatment.Materials and Methods: This retrospective study collected breast ultrasound images from two hospitals and formed training, test and external test sets after strict selection, which included 2,822, 707, and 210 ultrasound images, respectively. An optimized deep learning model (DLM) was constructed with the training set, and the performance was verified in both the test set and the external test set. Diagnostic results were compared with the BI-RADS categorization determined by radiologists. We divided breast cancer into different molecular subtypes according to hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression. The ability to predict molecular subtypes using the DLM was confirmed in the test set.Results: In the test set, with pathological results as the gold standard, the accuracy, sensitivity and specificity were 85.6, 98.7, and 63.1%, respectively, according to the BI-RADS categorization. The same set achieved an accuracy, sensitivity, and specificity of 89.7, 91.3, and 86.9%, respectively, when using the DLM. For the test set, the area under the curve (AUC) was 0.96. For the external test set, the AUC was 0.90. The diagnostic accuracy was 92.86% with the DLM in BI-RADS 4a patients. Approximately 70.76% of the cases were judged as benign tumors. Unnecessary biopsy was theoretically reduced by 67.86%. However, the false negative rate was 10.4%. A good prediction effect was shown for the molecular subtypes of breast cancer with the DLM. The AUC were 0.864, 0.811, and 0.837 for the triple-negative subtype, HER2 (+) subtype and HR (+) subtype predictions, respectively.Conclusion: This study showed that the DLM was highly accurate in recognizing breast tumors from ultrasound images. Thus, the DLM can greatly reduce the incidence of unnecessary biopsy, especially for patients with BI-RADS 4a. In addition, the predictive ability of this model for molecular subtypes was satisfactory,which has specific clinical application value.

ObjectivesComplement 1q binding protein (C1QBP/HABP1/p32/gC1qR) has been found to be overexpressed in triple-negative breast cancer (TNBC). However, the underlying mechanisms of high C1QBP expression and its role in TNBC remain largely unclear. Hypoxia is a tumor-associated microenvironment that promotes metastasis and paclitaxel (PTX) chemoresistance in tumor cells. In this study, we aimed to assess C1QBP expression and explore its role in hypoxia-related metastasis and chemoresistance in TNBC.Materials and MethodsRNA-sequencing of TNBC cells under hypoxia was performed to identify C1QBP. The effect of hypoxia inducible factor 1 subunit alpha (HIF-1α) on C1QBP expression was investigated using chromatin immunoprecipitation (ChIP) assay. The role of C1QBP in mediating metastasis, chemoresistance to PTX, and regulation of metastasis-linked vascular cell adhesion molecule 1 (VCAM-1) expression were studied using in vitro and in vivo experiments. Clinical tissue microarrays were used to verify the correlation of C1QBP with the expression of HIF-1α, VCAM-1, and RELA proto-oncogene nuclear factor-kappa B subunit (P65).ResultsWe found that hypoxia-induced HIF-1α upregulated C1QBP. The inhibition of C1QBP notably blocked metastasis of TNBC cells and increased their sensitivity to PTX under hypoxic conditions. Depletion of C1QBP decreased VCAM-1 expression by reducing the amount of P65 in the nucleus and suppressed the activation of hypoxia-induced protein kinase C-nuclear factor-kappa B (PKC-NF-κB) signaling.immunohistochemistry (IHC) staining of the tissue microarray showed positive correlations between the C1QBP level and those of HIF-1α, P65, and VCAM-1.ConclusionTargeting C1QBP along with PTX treatment might be a potential treatment for TNBC patients.

Spermatogonial stem cell (SSC) transplantation is an alternative reproductive method to achieve conservation and production of elite animals in livestock production. Creating a recipient animal without endogenous germ cells is important for effective SSC transplantation. However, natural mutants with depletion of SSCs are difficult to obtain, and drug ablation of endogenous germ cells is arduous to perform for practical use. In this study, we used mouse models to study the preparation of recipients with congenital germ cell ablation. We knocked out (KO) Ets-variant gene 5 (Etv5) in mice using the CRISPR/Cas9 system. The testicular weight of Etv5−/− mice was significantly lower than that of wild-type (WT) mice. The germ cell layer of the seminiferous tubules gradually receded with age in Etv5−/− mice. At 12 weeks of age, the tubules of Etv5−/− mice lacked almost all spermatogenic cells with a Sertoli cell-only phenotype, and sperm were completely absent in the epididymis. We subsequently transplanted allogeneic SSCs with enhanced green fluorescent protein (EGFP) into 3- (immature) or 7-week-old (mature) Etv5−/− mice. Partial restoration of germ cell layers in the seminiferous tubules and spermatogenesis was observed in all immature testes but not in mature adult testes at 2 months post-transplantation. The presence of heterologous genes Etv5 and EGFP in recipient testicular tissue and epididymal sperm by PCR indicated that sperm originated from the transplanted donor cells. Our study demonstrates that, although Etv5−/− mice could accommodate and support foreign germ cell transplantation, this process occurs in a quite low efficiency to support a full spermatogenesis of transplanted SSCs. However, using Etv5−/− mice as a recipient model for SSC transplantation is feasible, and still needs further investigation to establish an optimized transplantation process.

The existing test methods of geothermal tail water reinjection effect in sandstone geothermal reservoirs are not suitable for moderately deep and deep sandstone geothermal reservoirs, resulting in the poor filtration performance of fine-grained reservoirs. Therefore, a test method for the geothermal tail water reinjection effect in a moderately deep sandstone geothermal reservoir is proposed. This paper studies the static compatibility of raw water and geothermal tail water under different mixing ratios, determines the indexes affecting the reinjection effect of moderately deep sandstone geothermal reservoir tail water, analyzes the weight set of each influencing factor, and formulates a test standard for the reinjection effect of geothermal reservoir tail water. Finally, a tracer is selected to trace the reinjected tail water in the geothermal reservoir, and the tracer is used to obtain the result of each previously determined index. Eventually, the final reinjection effect of the geothermal tail water is obtained. The experimental results show that the fine-grade filtration performance, silt-grade filtration performance, and coarse-grade filtration performance of this method are improved compared with those of other methods; thus, the particle filtration performance is better, and the reinjection effect of geothermal reservoir tail water is better, which has a great significance for the geothermal resource exploitation of moderately deep sandstone.

When the typically utilized method for detecting the drilling conditions of high-temperature geothermal wells is applied, the detection takes a long time, the detection results are inconsistent with the actual conditions, and there are problems such as low detection efficiency and large detection deviation. Therefore, a method for detecting the drilling conditions of high-temperature geothermal wells described by a unit quaternion is proposed. Based on quaternion theory, the quaternion model of the position and attitude is constructed to obtain the drilling attitude. According to the analysis results and the basic principle of kernel principal component analysis, a model is built to realize the detection of high-temperature geothermal well drilling conditions. The experimental results show that in many iterations, the time required is stable and lower than that of other comparison methods, and the detection errors are all lower than 10%. The proposed method has high detection efficiency and low detection errors.

Astrocytes respond to central nervous system (CNS) insults with varieties of changes, such as cellular hypertrophy, migration, proliferation, scar formation, and upregulation of glial fibrillary acidic protein (GFAP) expression. While scar formation plays a very important role in wound healing and prevents further bleeding by forming a physical barrier, it is also one of key features of CNS injury, resulting in glial scar formation (astrogliosis), which is closely related to treatment resistant epilepsy, chronic pain, and other devastating diseases. Therefore, slowing the astrocytic activation process may give a time window of axonal growth after the CNS injury. However, the underlying mechanism of astrocytic activation remains unclear, and there is no effective therapeutic strategy to attenuate the activation process. Here, we found that methimazole could effectively inhibit the GFAP expression in physiological and pathological conditions. Moreover, we scratched primary cultures of cerebral cortical astrocytes with and without methimazole pretreatment and investigated whether methimazole could slow the healing process in these cultures. We found that methimazole could inhibit the GFAP protein expression in scratched astrocytes and prolong the latency of wound healing in cultures. We also measured the phosphorylation of extracellular signal-regulated kinase (ERK) in these cultures and found that methimazole could significantly inhibit the scratch-induced GFAP upregulation. For the first time, our study demonstrated that methimazole might be a possible compound that could inhibit the astrocytic activation following CNS injury by reducing the ERK phosphorylation in astrocytes.

This paper investigates the secure communication in a multi-pair massive multiple-input multiple-output (MIMO) amplify-and-forward (AF) relay network over Ricean fading channels in the presence of an eavesdropper. With the imperfect estimated channel state information, maximum ratio combining (MRC)/maximal ratio transmission (MRT) are employed for AF relaying. Based on random matrix theory, we first derive tractable analytical expressions of the end-to-end signal-to-interferenceplus-noise ratios (SINRs) at the intended user and Eve, respectively. Then, some asymptotic results for infinite Ricean K-factor, unbounded transmit power, and relay power are provided, which show that the SINRs at target user and Eve are both limited by some bounds and the effects of estimation error, relay noise, or received additive noise will be eliminated in these extreme cases. Meanwhile, power scaling laws for transmit power and relay power are studied that they should satisfy to maintain a desirable rate level. Analytical results indicate that the power can largely be cut down in inverse proportion to the number of relay antennas in Ricean fading channels. Moreover, by exploiting successive approximations, geometric programming, and iterative computation, a power control scheme is proposed to maximize the achievable sum secrecy rate. Numerical results are presented to demonstrate the effectiveness of this secure multi-pair massive MIMO relaying system.

Background/Aims: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. Methods: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. Results: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P

Edwardsiella ictaluri is known as the etiological agent of Red-head disease of yellow catfish (Pelteobagrus fulvidraco), and is the cause of heavy economic losses in the aquaculture industry. In this study, a Dot-Enzyme Linked Immunosorbent Assay (Dot-ELISA) and an Indirect Fluorescence Antibody technique (IFAT) for detecting Edwardsiella ictaluri were developed by using a monoclonal antibody, 5D11. For Dot-ELISA, the working dilutions of 5D11 and the secondary antisera (enzyme-labeled goat anti-mouse Ig) were 1:320 dilution and 1:3000 dilution, respectively. For IFAT, the working dilutions of 5D11 and goat-anti-mouse Ig conjugated with fluorescein isothiocyanate were as respectively 1:80 and 1:256. Both of the methods established were highly sensitivity (Minimum detectable concentration, 5 × 107 CFU/mL) and had a high degree of accuracy (positive rate was 100% for both artificial infected fish and spontaneous diseased Pelteobagrus fulvidraco). The two reliable methods developed have high potential for quick and efficient detection of Edwardsiella ictaluri in aquaculture production units.

With the continuous improvement of living standards, customers are gradually pursuing products which are individualization, entertainment, and scene. The production model of the enterprise has changed from the traditional inventory model to the manufacturing model driven by the customer orders. By analyzing the evolution process of customer to business, we get the overall framework of customer to business based on customer platform-connecting manufactory platform-connecting service. A case study in the automotive industry is introduced, which takes customer to business as the implementation of enterprise strategy. The detailed implementation process is discussed from the four aspects of open and networked demand for personalized customer (C), open and networked manufacturing (M), open and networked service (S), open and networked collaborative platform (P). The objective of this article is to provide general references for enterprises to change from traditional business-to-customer model to open and interconnected customization model by combining the improved customer-to-business framework and its application in automotive industry. The framework we put forward has achieved good results in related customer-to-business projects we participated in. The research results of this article can be used as a reference for enterprises to design, set, and carry out the model of customer to business.

Spermatogonial stem cell transplantation (SSCT) can restore male fertility through transfer of germline between donor and recipient males. From an agricultural perspective, SSCT could be an important next-generation reproductive and breeding tool in livestock production. Current SSCT approaches in large animals remain inefficient and many technical details need further investigation. This paper reviews the current knowledge on SSCT in large animals, addressing (1) donor spermatogonial stem cell (SSC) preparation, (2) recipient male treatment, and (3) SSC injection, homing, and detection. The major studies showing unequivocal evidence of donor SSC-derived spermatogenesis in large animals (mainly in livestock for breeding purpose) are summarized to discuss the current status of the field and future directions.

The trend towards socialization, personalization and servitization in smart manufacturing has attracted the attention of researchers, practitioners and governments. Social manufacturing is a novel manufacturing paradigm responding to this trend. However, the current cyber–physical system (CPS) merges only cyber and physical space; social space is missing. A cyber–physical–social system (CPSS)-based smart manufacturing is in demand, which incorporates cyber space, physical space and social space. With the development of the Internet of Things and social networks, a large volume of data is generated. A data-driven view is necessary to link tri-space. However, there is a lack of systematical investigation on the integration of CPSS and the data-driven view in the context of social manufacturing. This article proposes a seven-layered framework for a data-driven CPSS (D-CPSS) along the data–information–knowledge–wisdom (DIKW) pyramid under a social manufacturing environment. The evolution, components, general model and framework of D-CPSS are illustrated. An illustrative example is provided to explain the proposed framework. Detailed discussion and future perspectives on implementation are also presented.

To reduce the number of radio-frequency chains of base station, the use of finite resolution analog beamforming is desirbale in massive multiple-input multiple-output system. This article investigates the secure downlink massive multiple-input multiple-output data transmission with artificial noise at base station in the presence of a multi-antenna passive eavesdropper. The achievable user’s ergodic information rate and ergodic capacity of the eavesdropper are analyzed in detail, respectively. With maximum ratio transmission or maximum ratio combining, we derive closed-form expressions for a tight lower bound on ergodic secrecy rate and tight upper bound for secrecy outage probability. Based on these analytical expressions, the effects of various system parameters on secrecy performance, such as power allocation factor, number of eavesdropper’s antennas, number of the user terminals, total transmission power, and finite resolution analog beamforming parameters, are investigated in detail. Also, the optimal power allocation scheme between data and artificial noise signals is achieved in closed form to maximize the ergodic secrecy rate. In addition, we derive the conditions that the secure massive multiple-input multiple-output system need to meet to obtain a positive secrecy rate. Finally, numerical simulation results validate the system’s secrecy performance and verify all the theoretical analytical results.

This article studies the physical layer security of massive multiple-input multiple-output system in time-division-duplex mode. Specifically, a single-cell downlink massive multiple-input multiple-output communication system is considered. The resulting achievable secrecy rate is investigated in the presence of passive or active eavesdroppers. The analytical results reveal that the massive multiple-input multiple-output system is naturally immune to passive eavesdroppers, but will be dramatically degraded by active attack. On account of the risk caused by active attack, a simple and effective detection algorithm is proposed. Uplink pilots with random phases are transmitted during the detection operation. By comparing the phase deviation change of the received pilot signals’ cross product, the active eavesdroppers can be detected exactly. The closed-form expressions for probabilities of detection, false alarm, and false rejection are obtained respectively, which can demonstrate the robust performance of the proposed detection scheme. To maximize the secrecy energy efficiency of the system, the optimal power allocation strategy is studied under total power constraints. This optimization problem is efficiently solved by fractional programming. Numerical simulation results are derived to validate the secrecy performance of the massive multiple-input multiple-output system, the active pilot attacker detection performance, and the energy efficiency optimization effect.

LMB-100 is a mesothelin-targeted recombinant immunotoxin (iTox) that carries a modified Pseuodomonas exotoxin A (PE) payload. PE kills cells by inhibiting synthesis of new proteins. We found that treatment of pancreatic cancer cells with LMB-100 for 24⁻48 h did not change total protein level despite inducing protein synthesis inhibition (PSI). Further, increased levels of ubiquitinated proteins were detected, indicating that cells may have limited ability to compensate for PSI by reducing protein degradation. Together, these data suggest that PE depletes concentrations of a minority of cellular proteins. We used reverse phase protein array and Luminex assay to characterize this subset. LMB-100 decreased the abundance of 24 of 32 cancer-related proteins (including Bcl-x, Her2, Her3 and MUC16) without compensatory increases in other analytes. Further, cancer cells failed to maintain extracellular concentrations of cancer cell secreted growth factors (CCSGFs), including Vascular Endothelial Growth Factor (VEGF) following treatment with cytostatic LMB-100 doses both in culture and in mouse tumors. Decreased VEGF concentration did not change tumor vasculature density, however, LMB-100 caused tissue-specific changes in concentrations of secreted factors made by non-cancer cells. In summary, our data indicate that PSI caused by cytostatic LMB-100 doses preferentially depletes short-lived proteins such as oncogenic signaling molecules and CCSGFs.

ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene. Its mRNA expression is significantly low in many breast cancers; this is often associated with more aggressive phenotypes. However, the underlying molecular mechanism for its low expression has not been fully understood. This study was undertaken to evaluate the contribution of gene copy number variation, mutations, promoter methylation and histone modification to ARID1A's low expression. 38 pairs of breast invasive ductal carcinomas and their normal breast tissue counterparts from the same patients were randomly selected for gene expression and copy number variation detection. Promoter methylation and histone modification levels were evaluated by MeDIP-qPCR and ChIP-qPCR, respectively. PCR product Sanger sequencing was carried out to detect the exon mutation rate. Twenty-two out of 38 invasive ductal carcinomas in the study (57.9%) revealed ARID1A mRNA low expression by realtime RT-PCR. The relative promoter methylation level was, significantly higher in ARID1A mRNA low expression group compared with its high expression group (p

Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16(INK4a) and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLNexpressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. [ABSTRACT FROM AUTHOR]