Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.

BACKGROUND: Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited. AIM: To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer. METHODS: RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model. RESULTS: In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma. CONCLUSION: We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.

Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification.

Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.

PROTAC Prodrug-Integrated Nanosensitizer for Potentiating Radiation Therapy of Cancer.

Radiation therapy (RT) is one of the primary options for clinical cancer therapy, in particular advanced head and neck squamous cell carcinoma (HNSCC). Herein, the crucial role of bromodomain-containing protein 4 (BRD4)-RAD51 associated protein 1 (RAD51AP1) axis in sensitizing RT of HNSCC is revealed. A versatile nanosensitizer (RPB7H) is thus innovatively engineered by integrating a PROteolysis TArgeting Chimeras (PROTAC) prodrug (BPA771) and hafnium dioxide (HfO2) nanoparticles to downregulate BRD4-RAD51AP1 pathway and sensitize HNSCC tumor to RT. Upon intravenous administration, the RPB7H nanoparticles selectively accumulate at the tumor tissue and internalize into tumor cells by recognizing neuropilin-1 overexpressed in the tumor mass. HfO2 nanoparticles enhance RT effectiveness by amplifying X-ray deposition, intensifying DNA damage, and boosting oxidative stress. Meanwhile, BPA771 can be activated by RT-induced H2O2 secretion to degrade BRD4 and inactivate RAD51AP1, thus impeding RT-induced DNA damage repair. This versatile nanosensitizer, combined with X-ray irradiation, effectively regresses HNSCC tumor growth in a mouse model. The findings introduce a PROTAC prodrug-based radiosensitization strategy by targeting the BRD4-RAD51AP1 axis, may offer a promising avenue to augment RT and more effective HNSCC therapy.

Self-Adaptive Nanoregulator to Mitigate Dynamic Immune Evasion of Pancreatic Cancer.

The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator may provide a novel avenue for enhanced PDAC immunotherapy.

Ductular reaction in non-alcoholic fatty liver disease: When Macbeth is perverted.

Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatic carcinoma. NASH, characterized by hepatocyte injury, steatosis, inflammation, and fibrosis, is associated with NAFLD prognosis. Ductular reaction (DR) is a common compensatory reaction associated with liver injury, which involves the hepatic progenitor cells (HPCs), hepatic stellate cells, myofibroblasts, inflammatory cells (such as macrophages), and their secreted substances. Recently, several studies have shown that the extent of DR parallels the stage of NASH and fibrosis. This review summarizes previous research on the correlation between DR and NASH, the potential interplay mechanism driving HPC differentiation, and NASH progression.

Oral colon-targeted responsive alginate/hyaluronic acid-based hydrogel propels the application of infliximab in colitis.

Currently, commercialized infliximab (IFX) has rapidly propelled the clinical treatment of IBD, however, its inherent attributes, such as off-target effects and rapid metabolism, severely limit practical applications. Moreover, high doses injection of IFX can result in IBD treatment failure, which may induce other side effects. In this study, an colon microenvironment-responsive hydrogel (AL/HA hydrogel), consisting of acid-resistant sodium alginate and colon-degraded and targeted hyaluronic acid, was constructed by simple Ca2+/Zn2+ cross-linking. The ion-mediated hydrogel exhibited the protective effect of gastrointestinal tract to avoid early drug leakage, while the inflammation environments showed well-controlled drug release and significant biodegradable behaviors. Additionally, oral hydrogel exhibited long-standing enteritis areas compared with normal mice. Therefore, hydrogel-assisted enteritis treatment has great potential in IBD as an oral agent. After that, IFX was packaged in hydrogel to fabricate a facile oral antibody delivery system to treat IBD. IFX-embedded hydrogel showed remarkable therapeutic effect on IBD compared with free IFX. Surprisingly, oral hydrogel below 7 times IFX achieve the same amount of IFX-infused treatment that will further help alleviate the drawbacks of IFX. Our work elaborated on the efficacy of oral AL/HA@IFX in IBD, providing a guarantee for the future of promoted clinical transformation.

Nanovesicles loaded with a TGF-ß receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy.

The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-ß (TGF-ß) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-ß inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.

Association of LIPC polymorphisms with stroke risk in the Chinese population.

Background: Stroke is a common cerebrovascular disease. The purpose of this study was to explore the association between LIPC single nucleotide polymorphisms (SNPs) and the risk of stroke in the Chinese population. Methods: This study recruited 710 stroke patients and 701 healthy controls. The four SNPs (rs690, rs6083, rs3829461, and rs6074) in LIPC were genotyped by the Agena MassARRAY. The correlation between LIPC polymorphisms and stroke risk was measured by odds ratio (OR) and 95% confidence interval (CI). In addition, multifactor dimensionality reduction (MDR) analysis was used to evaluate the impact of SNP-SNP interaction on stroke risk. Results: Overall analysis showed that rs690 was associated with an increased risk of stroke (T vs. G: OR = 1.19, 95% CI: 1.01-1.40, p = 0.041; additive: OR = 1.20, 95% CI: 1.01-1.42, p = 0.036). The stratified analysis revealed that rs690 was associated with an increased risk of stroke in subjects aged ≤ 64 years, male patients, and smokers, and rs6074 was associated with an increased risk of stroke in subjects aged > 64 years, male patients, drinkers, and non-smokers (p < 0.05). The results of the MDR analysis suggested the four-locus model as the most favorable model for assessing the risk of stroke. The analysis of clinical parameters of stroke patients showed that rs690 was correlated with platelet distribution width (PDW) (p = 0.014) and hematocrit levels (p = 0.004), and rs6074 was correlated with low-density lipoprotein cholesterol (LDL-C) level (p = 0.033). Furthermore, bioinformatics analysis results demonstrated that the expression levels of LIPC and its related genes (APOB, CETP, PNPLA2, and LMF1) were significantly different between the control and stroke groups (p < 0.05), and LIPC-related proteins were mainly related to lipid metabolism. Conclusion: This study indicated that rs690 and rs6074 in LIPC were significantly associated with increased risk of stroke in the Chinese population, possibly by regulating the levels of PDW, HCT, and LDL-C.

Design of an activatable NIR-II nanoprobe for the in vivo elucidation of Alzheimer's disease-related variations in methylglyoxal concentrations.

Clear elucidation of the changes in Alzheimer's disease (AD)-related methylglyoxal (MGO) levels in vivo is significant yet highly challenging. Fluorescence imaging in the second near-infrared region (NIR-II, 1000-1700 nm) has gained increasing attention as an observation method in living organisms, but an MGO-activatable fluorescent probe that emits in this region for in vivo brain imaging is lacking because of the existence of the blood-brain barrier (BBB). Herein, a biocompatible Fe3O4 nanoparticle (IONP)-conjugated MGO-activatable NIR-II fluorescent probe (MAM) modified with the peptide T7 (HAIYPRH) (named TM-IONP) is reported for the in situ detection of MGO in a transgenic AD mouse model. In this system, the T7 peptide enhances BBB crossing and brain accumulation by specifically targeting transferrin receptors on the BBB. Due to the MAM probe, TM-IONPs emit fluorescence in the NIR-II region and display high selectivity with an MGO detection limit of 72 nM and a 10-fold increase in the fluorescence signal. After intravenous administration, the TM-IONPs are easily delivered to the brain and pass through the BBB without intervention, and as a result, the brains of AD mice can be noninvasively imaged for the first time by the in situ detection of MGO with a 24.2-fold enhancement in NIR-II fluorescence intensity compared with wild-type mice. Thus, this MGO-activated NIR-II-emitting nanoprobe is potentially useful for early AD diagnosis in clinic.

Self-Cooperative Prodrug Nanovesicles Migrate Immune Evasion to Potentiate Chemoradiotherapy in Head and Neck Cancer.

Chemoradiotherapy is the standard of care for the clinical treatment of locally advanced head and neck cancers. However, the combination of ion radiation with free chemotherapeutics yields unsatisfactory therapeutic output and severe side effects due to the nonspecific biodistribution of the anticancer drugs. Herein, a self-cooperative prodrug nanovesicle is reported for highly tumor-specific chemoradiotherapy. The nanovesicles integrating a prodrug of oxaliplatin (OXA) can passively accumulate at the tumor site and penetrate deep into the tumor mass via matrix metalloproteinase 2-mediated cleavage of the polyethylene glycol corona. The OXA prodrug can be restored inside the tumor cells with endogenous glutathione to trigger immunogenic cell death (ICD) of the tumor cells and sensitize the tumor to ion radiation. The nanovesicles can be further loaded with the JAK inhibitor ruxolitinib to abolish chemoradiotherapy-induced programmed death ligand 1 (PD-L1) upregulation on the surface of the tumor cells, thereby prompting chemoradiotherapy-induced immunotherapy by blocking the interferon gamma-Janus kinase-signal transducer and activator of transcription axis. The prodrug nanoplatform reported herein might present a novel strategy to cooperatively enhance chemoradiotherapy of head and cancer and overcome PD-L1-dependent immune evasion.

Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer.

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX2 NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX2) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX2 NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX2 in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.

Nonocular Influencing Factors for Primary Glaucoma: An Umbrella Review of Meta-Analysis.

INTRODUCTION: Glaucoma is the main cause of irreversible blindness worldwide. Still, little is known about nonocular risk factors. We use an umbrella review to examine the meta-analytic evidence of the correlation between nonocular factors and glaucoma. METHOD: We searched PubMed and Embase databases up to July 24, 2020. Eligible meta-analyses (MAs) included cohort, case-control, and randomized controlled study designs. Two authors independently extracted the data and evaluated the methodological quality of the MAs. AMSTAR 2 was used to assess the methodological quality of each included MA. RESULTS: This umbrella review contains 22 MAs with 22 unique nonocular factors in total. We identified 11 factors that increase the risk of glaucoma: hyperlipidemia, nocturnal dip in blood pressure, infection with Helicobacter pylori, myopia, obstructive sleep apnea syndrome, corneal properties, diabetes, hypertension, hypothyroidism, migraine, and plasma homocysteine. We identified 3 factors that reduce the risk of glaucoma: dietary intake of vitamin A, dietary intake of vitamin C, and short-term statin use. We identified 8 factors that had no association with glaucoma: dietary intake of vitamin B, dietary intake of vitamin E, cigarette smoking, Alzheimer's disease, serum folic acid, serum vitamin B6, serum vitamin B12, and serum vitamin D. CONCLUSIONS: In this umbrella review of MAs, evidence was found for associations of various nonocular factors with glaucoma to different degrees. However, risk factors were only mildly associated, suggesting low impact of systemic risk factors. Additional higher quality studies are needed to provide robust evidence.

Prolyl endopeptidase disruption reduces hepatic inflammation and oxidative stress in methionine-choline-deficient diet-induced steatohepatitis.

AIMS: Prolyl endopeptidase (PREP) is a serine endopeptidase widely distributed in the body, and accumulated evidence suggests that PREP participates in inflammation and oxidative stress. Here, we explored the effect of PREP gene disruption on hepatic inflammation and oxidative stress status in a methionine-choline-deficient (MCD)-induced nonalcoholic steatohepatitis (NASH) model. MAIN METHODS: PREP gene disruption (PREPgt) mice and wild-type (WT) littermates were placed on a control or an MCD diet for 4 weeks, respectively. The liver histopathological analysis and the number of inflammatory cells were determined by hematoxylin-eosin (HE) and immunohistochemical staining. Inflammation-associated genes and cytokine levels in liver tissue were evaluated by quantitative PCR and ELISA. The levels of P53, Sesn2, Nrf2, HO-1, and oxidative stress indicators in mice and the palmitic acid (PA)-treated human hepatocellular carcinoma cells (HepG2) were examined by immunoblotting and commercially available kits, respectively. KEY FINDINGS: We found that PREP expression was upregulated in the MCD-induced NASH model. In addition, PREP disruption alleviated MCD-induced hepatic inflammation accompanied by diminished infiltration of inflammatory cells and secretion of inflammatory mediators. More importantly, the results of this study indicate that targeting PREP can improve oxidative stress status in the liver of MCD-diet mice and PA-exposed HepG2 cells. The effect is most likely mediated by the activation of P53 and its downstream signaling pathways (Sesn2/Nrf2/HO-1). SIGNIFICANCE: Our results showed that PREP disruption (or inhibition) could decrease oxidative stress and inflammation and improve liver function, indicating that targeting PREP might be a new potential therapeutic option for NAFLD/NASH.

Spatio-Temporal Attention Model for Foreground Detection in Cross-Scene Surveillance Videos.

Foreground detection is an important theme in video surveillance. Conventional background modeling approaches build sophisticated temporal statistical model to detect foreground based on low-level features, while modern semantic/instance segmentation approaches generate high-level foreground annotation, but ignore the temporal relevance among consecutive frames. In this paper, we propose a Spatio-Temporal Attention Model (STAM) for cross-scene foreground detection. To fill the semantic gap between low and high level features, appearance and optical flow features are synthesized by attention modules via the feature learning procedure. Experimental results on CDnet 2014 benchmarks validate it and outperformed many state-of-the-art methods in seven evaluation metrics. With the attention modules and optical flow, its F-measure increased 9 % and 6 % respectively. The model without any tuning showed its cross-scene generalization on Wallflower and PETS datasets. The processing speed was 10.8 fps with the frame size 256 by 256.