Engineering Nanosensitizer to Remodel the TME for Hypoimmunogenic "Cold"-"Hot" Tumor Transformations.

α-PD-L1 therapy has shown encouraging results at harnessing the immune system to combat cancer. However, the treatment effect is relatively low due to the dense extracellular matrix (ECM) and tumor immunosuppressive microenvironment (TIME). Therefore, an ultrasound (US)-responsive nanosensitizer (URNS) is engineered to deliver losartan (LST) and polyethylenimine (PEI) to remolde the TME, driving "cold"-"hot" tumor transformation and enhancing the sensitivity of α-PD-L1 therapy. In the tumor site, noninvasive US can make MTNP generate ROS, which cleave ROS-sensitive bonds to dissociate MTNPtK@LST-PEI, shedding PEI and releasing LST from mesoporous spheres. The results demonstrated that URNS combined with α-PD-L1 therapy effectively inhibited tumor growth with an inhibition rate as high as 90%, which was 1.7-fold higher than that of the α-PD-L1 treatment in vivo. In summary, the URNS improves the sensitivity of α-PD-L1 therapy by remodeling the TME, which provides promising insights for optimizing cancer immunotherapy.

A Transformable Specific-Responsive Peptide for One-Step Synergistic Therapy of Bladder Cancer.

Synergistic therapy has shown greater advantages compared with monotherapy. However, the complex multiple-administration plan and potential side effects limit its clinical application. A transformable specific-responsive peptide (TSRP) is utilized to one-step achieve synergistic therapy integrating anti-tumor, anti-angiogenesis and immune response. The TSRP is composed of: i) Recognition unit could specifically target and inhibit the biological function of FGFR-1; ii) Transformable unit could self-assembly and trigger nanofibers formation; iii) Reactive unit could specifically cleaved by MMP-2/9 in tumor micro-environment; iv) Immune unit, stimulate the release of immune cells when LTX-315 (Immune-associated oncolytic peptide) exposed. Once its binding to FGFR-1, the TSRP could cleaved by MMP-2/9 to form the nanofibers on the cell membrane, with a retention time of up to 12 h. Through suppressing the phosphorylation levels of ERK 1/2 and PI3K/AKT signaling pathways downstream of FGFR-1, the TSRP significant inhibit the growth of tumor cells and the formation of angioginesis. Furthermore, LTX-315 is exposed after TSRP cleavage, resulting in Calreticulin activation and CD8+ T cells infiltration. All above processes together contribute to the increasing survival rate of tumor-bearing mice by nearly 4-folds. This work presented a unique design for the biological application of one-step synergistic therapy of bladder cancer.

LncRNA PVT1 promotes strong stemness and endothelial progenitor cell characteristics in renal carcinoma stem cells.

Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.

A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation.

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the "don't eat me" signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.

Lactate level as a predictor of outcomes in patients with acute upper gastrointestinal bleeding: A systematic review and meta­analysis.

There remains no consensus on the prognostic value of lactate in predicting adverse outcomes such as mortality, rebleeding and higher intensive care unit (ICU) admission rates in patients with upper gastrointestinal bleeding (UGIB). The present study aimed to determine the prognostic accuracy of lactate level in predicting adverse clinical outcomes in patients with acute UGIB. Systematic literature search was conducted in PubMed Central, SCOPUS, EMBASE, MEDLINE, Google Scholar and ScienceDirect databases for studies published up to February 2023. Random-effects model was used for the meta-analysis and the results were presented as pooled standardized mean differences or odds ratio (OR) with 95% confidence interval (CIs). A total of 11 studies were included in the present review. Most of the studies had a high risk of bias. Pooled OR were as follows: 1.39 (95% CI: 1.29-1.51; I2=85%) for the prediction of mortality; 1.29 (95% CI: 1.17-1.42; I2=85.9%) for prediction of ICU admission, 1.14 (95% CI: 1.06-1.23; I2=42.4%) for rebleeding and 2.84 (95% CI: 2.14-3.77; I2=8.1%) for the need of packed red blood cell (pRBC) transfusion. Sensitivity and specificity for the mortality prediction were 72% (95% CI: 57-83%) and 75% (95% CI: 61-85%), respectively, with the area under the curve of 0.79 (95% CI: 0.72-0.85). In conclusion, the results showed that lactate level is a moderately accurate early prediction marker of most adverse clinical outcomes such as mortality, rebleeding, ICU admission and the need for pRBC transfusion in acute UGIB patients.

Pyroptosis-Related Subtypes Predict the Response of Clear Cell Renal Cell Carcinoma to Targeted Therapy.

BACKGROUND: Pyroptosis plays a crucial role in anti-tumor immunity and in formation of the immune microenvironment. However, whether pyroptosis is involved in the progression of clear cell renal cell carcinoma (ccRCC) is still unclear. Personalized treatment of ccRCC requires detailed molecular classification to inform a specific therapy. METHODS: Molecular subtyping of ccRCC was performed based on consensus clustering of pyroptosis-related genes. The characteristics of these molecular subtypes were explored at the genome, transcriptome and protein levels. Single-cell RNA sequencing and CIBERSORT analysis were used to analyse the immune microenvironment of ccRCC, while Lasso regression was used to develop a prediction model based on hub genes. Expression of the pyroptosis-related gene GSDMB was also investigated at the tissue and cellular levels. RESULTS: Two molecular subtypes were identified based on the clustering of pyroptosis-related genes. Cluster 1 was associated with activation of classical oncogenic pathways, especially the angiogenesis pathway. Cluster 2 was associated with activation of immune-related pathways and high levels of immunosuppressive cells, exhausted CD8+ T cells, and tumor-associated fibroblast infiltration. Clusters 1 and 2 were thus defined as the angiogenic and inflamed subtypes, respectively. The two subtypes were predictive of the response of ccRCC to anti-angiogenic therapy and immunotherapy, with Cluster 1 patients benefiting from anti-angiogenic therapy and Cluster 2 patients showing better response to anti-PD1 inhibitor therapy. Furthermore, a 9-gene expression signature (HJURP, NUF2, KIF15, MELK, TPX2, PLK1, CDCA3, CTLA4, FOXP3) was identified that could predict outcome and response to immune checkpoint blockade therapy in test cohorts. Finally, GSDMB was found to be involved in the development of renal clear cell carcinoma. CONCLUSIONS: These results on pyroptosis-related genes in ccRCC provide a theoretical basis for understanding molecular heterogeneity and for the development of individualized treatment strategies.

An Ultrasound-Induced Self-Clearance Hydrogel for Male Reversible Contraception.

Nearly half of pregnancies worldwide are unintended mainly due to failure of contraception, resulting in negative effects on women's health. Male contraception techniques, primarily condoms and vasectomy, play a crucial role in birth control, but cannot be both highly effective and reversible at the same time. Herein, an ultrasound (US)-induced self-clearance hydrogel capable of real-time monitoring is utilized for in situ injection into the vas deferens, enabling effective contraception and noninvasive recanalization whenever needed. The hydrogel is composed of (i) sodium alginate (SA) conjugated with reactive oxygen species (ROS)-cleavable thioketal (SA-tK), (ii) titanium dioxide (TiO2), which can generate a specific level of ROS after US treatment, and (iii) calcium chloride (CaCl2), which triggers the formation of the hydrogel. For contraception, the above mixture agents are one-time injected into the vas deferens, which can transform from liquid to hydrogel within 160 s, thereby significantly physically blocking the vas deferens and inhibiting movability of sperm. When fertility is needed, a noninvasive remedial ultrasound can make TiO2 generate ROS, which cleaves SA-tK to destroy the network of the hydrogel. Owing to the recanalization, the refertility rate is restored to 100%. Meanwhile, diagnostic ultrasound (D-US, 22 MHz) can monitor the occlusion and recanalization process in real-time. In summary, the proposed hydrogel contraception can be a reliable, safe, and reversible male contraceptive strategy that addresses an unmet need for men to control their fertility.

Gestational Weight Gain and Its Effects on Maternal and Neonatal Outcome in Women With Twin Pregnancies: A Systematic Review and Meta-Analysis.

Background: The incidence of twin pregnancies has risen recently. Such pregnancies are associated with an increased risk for poor maternal and infant outcomes. Gestational weight gain, particularly in singleton pregnancies, has been well-linked with maternal and infant outcomes. The aim of the current meta-analysis was to evaluate the effects of gestational weight gain on maternal and fetal outcomes in women with twin pregnancies. Methods: A systematic search was conducted using the PubMed, Scopus, and Google Scholar databases. Studies, either retrospective or prospective in design, evaluating the effects of gestational weight gain (defined using Institute of Medicine (IOM) guidelines) maternal and/or fetal/neonatal outcomes in women with twin pregnancies were included. Statistical analysis was performed using STATA software. Results: Eleven studies were included in the meta-analysis. Mothers with inadequate weight gain had increased risk for gestational diabetes mellitus (OR 1.19; 95% CI: 1.01, 1.40) and decreased risk for gestational hypertension (OR 0.58; 95% CI: 0.49, 0.68) and cesarean section (OR 0.94; 95% CI: 0.93, 0.96). Neonates born to mothers with inadequate weight gain were susceptible to increased risk for preterm delivery (OR 1.17; 95% CI: 1.03, 1.34), very preterm delivery (gestational age <32 weeks) (OR 1.84; 95% CI: 1.36, 2.48), small for gestational age status (OR 1.41; 95% CI: 1.15, 1.72), low birth weight status (<2,500 g) (OR 1.27; 95% CI: 1.17, 1.38), and neonatal intensive care unit (NICU) admission (OR 1.16; 95% CI: 1.08, 1.24). The pooled findings indicate an increased risk for gestational hypertension (OR 1.82; 95% CI: 1.60, 2.06) and cesarean section (OR 1.07; 95% CI: 1.05, 1.08) among mothers with excessive weight gain. Neonates born to mothers with excessive weight gain were susceptible to increased risk for preterm delivery and very preterm delivery, but were associated with a decreased risk for low birth weight status and small for gestational age status. Conclusions: Gestational weight gain in twin pregnancy, either lower or higher than IOM recommended guidelines, is associated with poor maternal and neonatal outcomes. Our findings call for incorporating counseling on optimal weight gain during pregnancy as part of routine antenatal visits.