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BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

MEDI2228 is an antibody drug conjugate (ADC) comprised of a fully human B-cell maturation antigen (BCMA) antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer. This phase 1 trial evaluated MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma (MM), who received prior treatment with approved agents from 3 classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies). Primary endpoint was safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. A total of 107 patients were treated and the maximum tolerated dose (MTD) was 0.14 mg/kg Q3W. Two patients had dose-limiting toxicities (DLTs; thrombocytopenia; 0.20 mg/kg Q3W). The most frequent treatment-related adverse events were photophobia (43.9%), rash (29.0%), and thrombocytopenia (19.6%). In MTD cohort A (n = 41), the objective response rate (ORR) was 56.1%, with 1 stringent complete response, 9 very good partial responses, and 13 partial responses. ORR was 53.3% in triple refractory patients. In cohort B (n=25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug. KEY POINTS: MEDI2228 is an ADC comprised of a fully human anti-BCMA antibody conjugated to the cytotoxic PBD payload, tesirine. MEDI2228 monotherapy demonstrated efficacy across all dose levels; and responses were observed in patients with triple refractory MM. This study further validates BCMA as a target for ADC-based therapy in MM; ocular toxicity precluded further clinical development. [ABSTRACT FROM AUTHOR]

Hepatocyte-derived liver progenitor-like cells (HepLPCs) exhibit a remarkable capacity to support liver function by detoxifying ammonia, promoting native liver regeneration, and suppressing inflammation, which leads to improvements in the recovery and survival of animals with acute liver failure (ALF). However, the mechanism through which HepLPCs promote liver regeneration is unclear. Here, we isolated HepLPC-derived extracellular vesicles (HepLPC-EVs) from conditioned media and performed microRNA sequencing analysis. Our results showed HepLPC-EVs promoted liver regeneration in mice with carbon tetrachloride or acetaminophen induced ALF. Cell cycle progression and proliferation of primary human hepatocytes were promoted after coculture with HepLPC-EVs. Exosomal miRNA sequencing confirmed that HepLPC-EVs were enriched with miR-183-5p, which played an essential role in ameliorating ALF. Mechanistically, HepLPC-derived exosomal miR-183-5p negatively regulated the expression of the target gene FoxO1, activated the Akt/GSK3β/β-catenin signaling pathway, and thereby promoted liver regeneration and restoration of normal liver function. These results indicate that during ALF, HepLPC-Exos mediate liver regeneration mainly through a paracrine exosome-dependent mechanism and these effects accelerate liver regeneration and lead to the restoration of normal liver function. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the fertility history and demand for reproductive health services of new residents in Shanghai.MethodsA questionnaire survey was conducted among 1 358 new residents in 36 survey sites in 7 districts of Shanghai from July to September 2020. The content includes fertility history， induced abortion history， demand for reproductive health-related services， awareness rate of the Shanghai Family Planning Association and service access rate， etc.ResultsAmong the new residents themselves and their spouses/sexual partners， 31.3% （374/1 194） had been pregnant once and 33.6% （401/1 194） had been pregnant twice； 46.3% （533/1 194）had one child and 29.7% （355/1 194）had two children. The difference of number of births among new residents with different residence time， those who did or did not possess permanent residency or residence permits， and those from different sources （urban or rural） was statistically significant （χ2=158.664， 50.263， 16.011， 114.419， all P

Sugarcane smut, caused by Sporisorium scitamineum, poses a significant threat to sugarcane production in China, resulting in substantial economic losses. This study aims to understand the resistance of sugarcane genotypes to smut and the relationship between smut incidence and yield loss during ratoon cropping. We evaluated the smut resistance of 169 sugarcane genotypes. We assessed the combining ability of nine female and six male parent plants in field trials conducted from 2019 to 2022 in Fusui or Longzhou, China. Our findings reveal increased smut incidence with each successive ratoon cycle, particularly after the second ratoon. Smut infection during the ratoon cycle reduced sugarcane yield by decreasing the number of millable stalks. Variance analysis indicated that genotype, cropping cycle, and location significantly influenced disease incidence. Based on resistance levels, the genotypes were categorized into five groups: 10 highly resistant, 37 resistant, 38 moderately susceptible, 42 susceptible, and 42 highly susceptible. Analysis of general combining ability (GCA) and specific combining ability (SCA) demonstrated that crossing sugarcane parents with smut resistance effectively produced resistant hybrid offspring. Additionally, the maternal inheritance effect was more pronounced than the paternal inheritance effect, indicating that using a resistant genotype as the maternal parent is more advantageous for enhancing smut resistance. These results provide valuable insights into sugarcane smut resistance, aiding in selecting parental lines and breeding new resistant varieties. [ABSTRACT FROM AUTHOR]

Sylvester matrix equations play important roles in control and system theory. We consider a class of the generalized coupled Sylvester quaternion matrix equations, which includes a lot of special matrix equations such as Stein matrix equation, Lyapunov matrix equation and Sylvester matrix equation on the quaternion skew field. First, the quaternion Krylov subspace and its F-orthogonal basis are constructed via a new quaternion matrix product and the global quaternion Arnoldi process. Then a global quaternion generalized minimal residual (Gl-QGMRES) method is proposed for solving the generalized coupled Sylvester quaternion matrix equations. The convergence of the proposed method is theoretically analysed. Finally, the effectiveness and feasibility of the proposal are verified by some numerical experiments. As an application of Gl-QGMRES method, we establish a kind of colour image encryption and decryption by embedding watermark images. [ABSTRACT FROM AUTHOR]

This study aims to investigate and compare the determinants of gender preference for children in rural and urban China under the values of children to parents (VOC) approach by focusing on the effects of attitudes to elder care and gender roles, and the attainment of insurance programs. Using pooled cross-sectional data from 2013 and 2015 of the Chinese General Social Surveys, we found that rural individuals expecting children responsible for old-age support exhibit daughter preference, followed by balance preference, whereas their urban counterparts show similar son preference and daughter preference. In addition, balance preference is associated with traditional gender role attitudes among rural individuals but correlated with more equal gender attitudes among urbanites. Furthermore, having more economic security decreases rural individuals' preferences for having more daughters. The findings suggest that the prevalent balance preference and the rising preference for daughters have quite different implications on the gender relationship between rural and urban China, and traditionalism still drives gender preference in rural China. Policy implications are also discussed. [ABSTRACT FROM AUTHOR]

Sugarcane midrib red rot caused by Colletotrichum falcatum is widespread in China. Standardizing the resistance evaluation methods and screening resistant varieties against this disease is crucial. C. falcatum was determined as the causal agent of midrib red rot by isolating and identifying pathogenic fungi from diseased leaves in Guangxi, China. A field trial of 237 sugarcane genotypes was conducted for three consecutive years to investigate disease incidence and indices for three experimental sites in Guangxi. The combined analysis of variance showed that disease incidence was significantly affected by genotype, year, location and their interactions. Cluster and discriminant analysis showed that 237 sugarcane genotypes were classified into five categories, including 20 as highly resistant, 82 as resistant, 71 as moderately susceptible, 46 as susceptible and 18 as highly susceptible. This study has enhanced our understanding of sugarcane resistance to midrib red rot, selected disease‐resistant parents and laid the foundation for developing elite disease‐resistant varieties. [ABSTRACT FROM AUTHOR]