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Anaerobic bacteria and facultative anaerobe are usually used as delivery carriers of antitumor drugs because of their tumor hypoxia targeting and antitumor immune activation abilities, but suffer from dose-dependent systemic side effects. Here, engineered probiotics Nissle 1917 (EcN-T) were constructed for in-situ synthesis of melanin in tumor region for enhanced photothermal therapy (PTT) combining with immunotherapy. By means of genetic engineering, EcN-T that could highly express tyrosinase under near-infrared (NIR) light irradiation were constructed. Due to their intrinsic tumor hypoxia targeting, EcN-T could accumulate and rapidly proliferate in tumor region after intravenous injection. Tyrosinase expression for the following melanin biosynthesis within tumor could be initiated upon NIR exposure. Hyperbaric oxygen treatment facilitated the oxidation of tyrosine to promote the generation of melanin in situ, giving robust photothermal performance to induce immunogenic tumor cell death. Assited by immunostimulatory responses of EcN, maturation of dendritic cells and priming of cytotoxic T cells were largely promoted in tumor tissue, resulting in significant inhibition of tumor growth and recurrence. This bacteria-mediated combined therapeutic strategy showed high efficacy and good safety. By means of genetic engineering and synthetic biology, engineered probiotics Nissle 1917 (EcN-T) which show excellent tumor targeting and proliferation abilities are constructed for in-situ synthesis of melanin in tumor region induced by NIR light irradiation and HBO treating. Upon light exposure, considerable heat can be generated to induce immunogenic tumor cell death. Assited by immunostimulatory responses of EcN, maturation of dendritic cells and priming of cytotoxic T cells are largely promoted in tumor tissue, giving significant inhibition of tumor growth and recurrence. [Display omitted] • Engineered probiotics Nissle 1917 can intracellularly produce melanin with excellent photothermal performance. • Engineered probiotics Nissle 1917 can rapidly proliferate and homogenously distribute in tumor region. • Melanin biosynthesis within tumor can be initiated upon external NIR exposure. • Hyperbaric oxygen can promote the generation of melanin within tumor. [ABSTRACT FROM AUTHOR]

• Temperature exposure during pregnancy may increase risk of preeclampsia. • High pre-pregnancy BMI may increase sensitivity to temperature exposure. • Gestational weeks 1 – 8 of pregnancy are vulnerable to temperature exposure. Environmental exposures during pregnancy have been associated with adverse obstetric outcomes. However, limited and inconsistent evidence exists regarding the association between air temperature exposure and the risk of preeclampsia (PE). This study aimed to evaluate the correlation between ambient temperature exposure during pregnancy and PE risk, as well as identify the specific time window of temperature exposure that increases PE risk. A population-based cohort study was conducted from January 2012 to April 2022 in Guangzhou, China. Pregnant women were recruited in early pregnancy and followed until delivery. A total of 3,314 PE patients and 114,201 normal pregnancies were included. Ambient temperature exposures at different gestational weeks were recorded for each participant. Logistic regression models were used to evaluate the correlation between ambient temperature exposure and PE risk. Stratified analyses were conducted based on maternal age and pre-pregnancy BMI. Distributed lag models were employed to identify the time window of temperature exposure related to PE. Exposure to extreme high temperature (aOR = 1.24, 95 % CI 1.12 – 1.38) and moderate high temperature (aOR = 1.22, 95 % CI 1.10 – 1.35) during early pregnancy was associated with an increased risk of PE. Furthermore, women with higher pre-pregnancy BMI had a higher risk of developing PE when exposed to high temperature during early pregnancy compared to normal-weight women. The time window of temperature exposure related to PE was identified as pregnancy weeks 1 to 8. This study provides evidence for the association of high temperature exposure during early pregnancy with the risk of PE, as well as identifies the specific time window of temperature exposure related to PE. These findings have implications for developing potential strategies to protect pregnant women, particularly those with higher pre-pregnancy BMI, from the adverse effects of extreme temperatures during early pregnancy. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) occurs in the urinary system which has high incidence and mortality. During past decades, lots of long noncoding RNAs (lncRNAs) have been identified to function in cancer progression, including BC. In our research, we targeted at investigating the functions and mechanisms of lncRNA pro-transition associated RNA (PTAR) in BC. Functional assays were implemented to access the changes of BC cell phenotype. Mechanistic assays were applied for confirming the interaction between RNAs. Based on the collected data, PTAR expression was high in BC cells and silenced PTAR repressed BC cell proliferative, migratory and invasive abilities but improved cell apoptotic ability. In vivo study also verified PTAR depletion inhibited BC tumor growth. Furthermore, miR-299–3p was confirmed to bind with PTAR and its overexpression suppressed malignant behaviors of BC cells. Cluster of differentiation 164 (CD164) was proved to be miR-299–3p target. Rescue experiments implied overexpressed CD164 offset the inhibitory function of PTAR depletion on BC cell phenotype. Additionally, CD164 was uncovered to combine with C-X-C motif chemokine receptor 4 (CXCR4) to switch on PI3K/AKT pathway. To conclude, PTAR facilitates BC development via regulating miR-299–3p/CD164 axis and activating PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocyte (CTL), a key effector cell in aplastic anemia (AA) immune injury, is shown to be a potential target for AA drug therapy. However, there is no candidate for this target till now. Oriented by the inhibition activity of CTL and macrophage derived nitric oxide (NO), a series of novel sinomenine derivatives on rings A and C are designed, synthesized and screened. Among them, compound 3a demonstrates the best inhibitory activity on CTL with an IC 50 value of 2.3 μM, and a 97.1% inhibiton rate on macrophage NO production without significant cytotoxicity. Further, compound 3a exhibits substantial therapeutic efficacy on immune-mediated BM failure in AA model mice by improving the symptoms of anemia and the function of BM hematopoiesis, and shows more advantages in life quality improving than cyclosporine A (CsA). Its efficacy on AA at least partly comes from targeting on activated cluster of differentiation (CD)8+ T cell. Additionally, 3a also shows much less toxicity (LD 50 > 10.0 g/kg) than sinomenine (LD 50 = 1.1 g/kg) in preliminary acute toxicity assessment in mice, and has a low risk to inhibit hERG to cause cardiotoxicity. These results indicate that compound 3a merits further investigation for AA treatment by targeting on CTL. [Display omitted] • A series of novel sinomenine derivatives are designed and synthesized. • 3a shows the best in vitro inhibitory activity. • 3a shows substantial therapeutic efficacy on mice model of aplastic anemia. • The efficacy of 3a at least partly comes from targeting on activated CD8+ T cell. • 3a shows good safety in vivo. [ABSTRACT FROM AUTHOR]