IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia.

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1ß mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

Automated machine learning for early prediction of acute kidney injury in acute pancreatitis.

BACKGROUND: Acute kidney injury (AKI) represents a frequent and grave complication associated with acute pancreatitis (AP), substantially elevating both mortality rates and the financial burden of hospitalization. The aim of our study is to construct a predictive model utilizing automated machine learning (AutoML) algorithms for the early prediction of AKI in patients with AP. METHODS: We retrospectively analyzed patients who were diagnosed with AP in our hospital from January 2017 to December 2021. These patients were randomly allocated into a training set and a validation set at a ratio of 7:3. To develop predictive models for each set, we employed the least absolute shrinkage and selection operator (LASSO) algorithm along with AutoML. A nomogram was developed based on multivariate logistic regression analysis outcomes. The model's efficacy was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Additionally, the performance of the model constructed via AutoML was evaluated using decision curve analysis (DCA), feature importance, SHapley Additive exPlanations (SHAP) plots, and locally interpretable model-agnostic explanations (LIME). RESULTS: This study incorporated a total of 437 patients who met the inclusion criteria. Out of these, 313 were assigned to the training cohort and 124 to the validation cohort. In the training and validation cohorts, AKI occurred in 68 (21.7%) and 29(23.4%) patients, respectively. Comparative analysis revealed that the AutoML models exhibited enhanced performance over traditional logistic regression (LR). Furthermore, the deep learning (DL) model demonstrated superior predictive accuracy, evidenced by an area under the ROC curve of 0.963 in the training set and 0.830 in the validation set, surpassing other comparative models. The key variables identified as significant in the DL model within the training dataset included creatinine (Cr), urea (Urea), international normalized ratio (INR), etiology, smoking, alanine aminotransferase (ALT), hypertension, prothrombin time (PT), lactate dehydrogenase (LDH), and diabetes. CONCLUSION: The AutoML model, utilizing DL algorithm, offers considerable clinical significance in the early detection of AKI among patients with AP.

Metal-polyphenol "prison" attenuated bacterial outer membrane vesicle for chemodynamics promoted in situ tumor vaccines.

As natural adjuvants, the bacterial outer membrane vesicles (OMV) hold great potential in cancer vaccines. However, the inherent immunotoxicity of OMV and the rarity of tumor-specific antigens seriously hamper the clinical translation of OMV-based cancer vaccines. Herein, metal-phenolic networks (MPNs) are used to attenuate the toxicity of OMV, meanwhile, provide tumor antigens via the chemodynamic effect induced immunogenic cell death (ICD). Specifically, MPNs are assembled on the OMV surface through the coordination reaction between ferric ions and tannic acid. The iron-based "prison" is locally collapsed in the tumor microenvironment (TME) with both low pH and high ATP features, and thus the systemic toxicity of OMV is significantly attenuated. The released ferric ions in TME promote the ICD of cancer cells through Fenton reaction and then the generation of abundant tumor antigens, which can be used to fabricate in-situ vaccines by converging with OMV. Together with the immunomodulatory effect of OMV, potent tumor repression on a bilateral tumor model is achieved with good biosafety.

In Vivo Imaging for the Visualization of Extracellular Vesicle-Based Tumor Therapy.

Extracellular vesicles (EVs) exhibiting versatile biological functions provide promising prospects as natural therapeutic agents and drug delivery vehicles. For future clinical translation, revealing the fate of EVs in vivo, especially their accumulation at lesion sites, is very important. The continuous development of in vivo imaging technology has made it possible to track the real-time distribution of EVs. This article reviews the applications of mammal-, plant-, and bacteria-derived EVs in tumor therapy, the labeling methods of EVs for in vivo imaging, the advantages and disadvantages of different imaging techniques, and possible improvements for future work.

Comprehensive analyses of PDHA1 that serves as a predictive biomarker for immunotherapy response in cancer.

Recent studies have proposed that pyruvate dehydrogenase E1 component subunit alpha (PDHA1), a cuproptosis-key gene, is crucial to the glucose metabolism reprogram of tumor cells. However, the functional roles and regulated mechanisms of PDHA1 in multiple cancers are largely unknown. The Cancer Genome Atlas (TCGA), GEPIA2, and cBioPortal databases were utilized to elucidate the function of PDHA1 in 33 tumor types. We found that PDHA1 was aberrantly expressed in most cancer types. Lung adenocarcinoma (LUAD) patients with high PDHA1 levels were significantly correlated with poor prognosis of overall survival (OS) and first progression (FP). Kidney renal clear cell carcinoma (KIRC) patients with low PDHA1 levels displayed poor OS and disease-free survival (DFS). However, for stomach adenocarcinoma (STAD), the downregulated PDHA1 expression predicted a good prognosis in patients. Moreover, we evaluated the mutation diversity of PDHA1 in cancers and their association with prognosis. We also analyzed the protein phosphorylation and DNA methylation of PDHA1 in various tumors. The PDHA1 expression was negatively correlated with tumor-infiltrating immune cells, such as myeloid dendritic cells (DCs), B cells, and T cells in pan-cancers. Mechanically, we used single-cell sequencing to discover that the PDHA1 expression had a close link with several cancer-associated signaling pathways, such as DNA damage, cell invasion, and angiogenesis. At last, we conducted a co-expressed enrichment analysis and showed that aberrantly expressed PDHA1 participated in the regulation of mitochondrial signaling pathways, including oxidative phosphorylation, cellular respiration, and electron transfer activity. In summary, PDHA1 could be a prognostic and immune-associated biomarker in multiple cancers.

Correlations of ALD, Keap-1, and FoxO4 expression with traditional tumor markers and clinicopathological characteristics in colorectal carcinoma.

Aldolase A (A-2) (ALD), Kelch-like-ECH associated protein-1 (Keap-1), and Forkhead box O4 (FoxO4) are key regulatory proteins, which have been proven to be involved in tumor development. However, the clinicopathological significance of ALD, Keap-1, and FoxO4 expressions in colorectal (colon) carcinoma (CRC) is not clearly known. We sought to explore the clinicopathological significance of ALD, Keap-1, and FoxO4 in CRC to provide evidences for potential monitoring index of CRC. Cases of 199 CRC patients were analyzed retrospectively. Evaluation of ALD, cAMP response element-binding protein-2, cyclo-oxygenase 2, FoxO4, Keap-1, and p53 expressions in CRC patients was accomplished with immunohistochemical technique. The patients were divided into negative and positive groups in accordance with immunohistochemical result. We compared the clinicopathological characteristics of the patients in the 2 groups, coupled with analysis of the relationship between 6 aforesaid proteins and clinicopathological characteristics. Herein, we confirmed the association of tumor location with the expression of ALD, Keap-1, and FoxO4. Also, tumor differentiation was observed to associate significantly with the expression of Keap-1, FoxO4, and Cox-2. The data also revealed that there was a correlation between smoking and expression of ALD, Keap-1, FoxO4, p53, and Cox-2. Nevertheless, insignificant difference was observed when clinicopathological characteristics were compared with cAMP response element-binding protein-2 expression. These findings suggest that ALD, Keap-1, and FoxO4 reinvolved in CRC development, and thus may be considered as potential monitoring protein for CRC.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

Long-term treatment of Nicotinamide mononucleotide improved age-related diminished ovary reserve through enhancing the mitophagy level of granulosa cells in mice.

Ovarian aging affects the reproductive health of elderly women due to decline in oocyte quality, which is closely related to mitochondrial dysfunction. Nicotinamide mononucleotide (NMN), as a precursor of NAD+, effectively regulate mitochondria metabolism in mice. However, roles of NMN in improving age-related diminished ovary reserve remain to be determined. In present study, 4, 8, 12, 24, 40-week old female ICR mice were collected and a 20-week-long administration of NMN was conducted to 40-week-old mice (60WN), meanwhile the control group is given water (60WC). First, we found that 20-week-long administration of NMN to 40-week-old mice exhibited anti-aging and anti-inflammatory effects on organ structures, along with the improvement of estrus cycle condition and endocrine function. The number of primordial, primary, secondary, antral follicles and corpora luteum of ovaries in 60WN group was significantly increased compared with those in 60WC group. Additionally, the protein and gene expressions of P16 of ovaries were significantly reduced in 60WN group than in 60WC group. the mitochondria biogenesis, autophagy level, and proteases activity enhanced in granulosa cells after 20-week-administration of NMN. Present results indicate that NMN has the potential to save diminished ovary reserve by long-term treatment, providing a basis for exploring the role of NMN in anti-ovarian aging by enhancing the mitophagy level of granulosa cells.

Clinical characteristics and risk factors of Talaromyces marneffei infection in human immunodeficiency virus-negative patients: A retrospective observational study.

BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). CONCLUSIONS: Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.

Low dose contrast media in step-and-shoot coronary angiography with third-generation dual-source computed tomography: feasibility of using 30 mL of contrast media in patients with body surface area <1.7 m2.

BACKGROUND: Reducing contrast media volume in coronary computed tomography angiography minimizes the risk of adverse events but may compromise diagnostic image quality. We aimed to evaluate coronary computed tomography angiography's diagnostic image quality while using 30 mL of contrast media in patients with a body surface area <1.7 m2. METHODS: This prospective study included patients who underwent coronary computed tomography angiography from May 2018 to June 2019. The patients were divided into a low-dose group, who received 30 mL of contrast media, and a routine-dose group, who received contrast media based on body weight. Patient characteristics, coronary computed tomography angiography results, and quantitative and qualitative image results were assessed and compared. RESULTS: In total, 103 patients with a body surface area <1.7 m2 were 53 in the low-dose group and 50 in the routine-dose group. Sex, age, body surface area, body weight, and heart rate were similar between the groups (P>0.05). A contrast media volume of 30±0 mL was used for the low-dose group, and 41.62±4.59 mL was used for the routine-dose group. The low-dose group's computed tomography values were significantly different from those of the routine-dose group (P<0.05). The radiologists demonstrated agreement regarding diagnostic image quality and accuracy (kappa =0.91 and 0.85, respectively). CONCLUSIONS: Using 30 mL of contrast media for coronary computed tomography angiography in patients with a body surface area <1.7 m2 provided a suitable diagnostic image quality for coronary artery disease diagnosis. Although radiation doses were similar between the groups, the decreased contrast media volume was likely beneficial for the patients.

Protective effects of recombinant 53-kDa protein of Trichinella spiralis on acute lung injury in mice via alleviating lung pyroptosis by promoting M2 macrophage polarization.

Trichinella spiralis represents an effective treatment for autoimmune and inflammatory diseases. The effects of recombinant T. spiralis (TS) 53-kDa protein (rTsP53) on acute lung injury (ALI) remain unclear. Here, mice were divided randomly into a control group, LPS group, and rTsP53 + LPS group. ALI was induced in BALB/c mice by LPS (10 mg/kg) injected via the tail vein. rTsP53 (200 µl; 0.4 µg/µl) was injected subcutaneously three times at an interval of 5 d before inducing ALI in the rTsP53+LPS group. Lung pathological score, the ratio and markers of classic activated macrophages (M1) and alternatively activated macrophages (M2), cytokine profiles in alveolar lavage fluid, and pyroptosis protein expression in lung tissue were investigated. RTsP53 decreased lung pathological score. Furthermore, rTsP53 suppressed inflammation by increasing IL-4, IL-10, and IL-13. There was an increase in alveolar M2 macrophage numbers, with an increase in CD206 and arginase-1-positive cells and a decrease in alveolar M1 markers such as CD197 and iNOS. In addition, the polarization of M2 macrophages induced by rTsP53 treatment could alleviate ALI by suppressing lung pyroptosis. RTsP53 was identified as a potential agent for treating LPS-induced ALI via alleviating lung pyroptosis by promoting M2 macrophage polarization.

Can the Coronary Artery Calcium Score Scan Reduce the Radiation Dose in Coronary Computed Tomography Angiography?

RATIONALE AND OBJECTIVES: Radiation exposure from coronary computed tomography angiography (CCTA) remains a cause for concern. The objective of this study was to investigate whether using the coronary artery calcium score scan (CACS) would reduce the radiation dose for CCTA scanning and the overall radiation exposure (ORE). MATERIALS AND METHODS: In total, 256 patients were examined with a third-generation dual-source CT (n = 200) or 256-row CT (n = 56), among whom 105 (Group A) and 28 patients (Group B), respectively, underwent CCTA with CACS for field of view planning. The remaining patients, with the scout view for field of view planning, constituted Group A1 and B1. The scanning parameter settings were standardized between groups. RESULTS: Shorter scan lengths were observed in Group A (9.98 ± 0.79 cm) compared to Group A1 (13.64 ± 1.79 cm; p < 0.001), which also resulted in a lower dose-length product (DLP) in Group A (115.04 ± 64.13) relative to Group A1 (138.67 ± 68.87; p < 0.05). Similarly, shorter scan lengths were found in Group B (14.92 ± 1.17 cm) compared to Group B1 (15.79 ± 0.63 cm; p = 0.001); this resulted in a lower DLP (322.07 ± 45.39) compared to Group B1 (354.34 ± 65.27; p = 0.036). The CACS resulted in an increase in ORE in both groups. CONCLUSION: CACS may have a critical role in the reduction of radiation dose in CCTA scanning, but the potential effectiveness of CACS in reducing ORE is weak.

Responsive Exosome Nano-bioconjugates for Synergistic Cancer Therapy.

Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize responsive exosome nano-bioconjugates for cancer therapy. Azide-modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH-sensitive linkers. After systemic administration, the nano-bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic-imine bonds of the nano-bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished "don't eat me" signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro-tumoral M2 to anti-tumoral M1.

Biocompatible Heat-Shock Protein Inhibitor-Delivered Flowerlike Short-Wave Infrared Nanoprobe for Mild Temperature-Driven Highly Efficient Tumor Ablation.

Multifunctional nanomaterials for dual-mode imaging guided cancer therapy are highly desirable in clinical applications. Herein, a flowerlike NiS2-coated NaLuF4:Nd (Lu:Nd@NiS2) nanoparticle was synthesized as a novel therapeutic agent for short-wave infrared light imaging and magnetic resonance imaging to guide photothermal therapy (PTT). The material was then loaded with phenolic epigallocatechin 3-gallate (EGCG), which is a natural heat-shock protein 90 (HSP90) inhibitor. Upon near infrared irradiation, EGCG was released from the Lu:Nd@NiS2-EGCG, which bound HSP90 and reduced cell tolerance to heat, resulting in a better therapeutic effect at the same elevated temperature. Therefore, with minimal side effects and remarkable antitumor efficacy in vivo, Lu:Nd@NiS2-EGCG appeared to be a promising photothermal agent for enhanced PTT.

Green synthesis of ultra-small VOx nanodots for acidic-activated HSP60 inhibition and therapeutic enhancement.

Using metal oxide semiconductor nanomaterials for synergistic cancer treatment has recently attracted the attention of numerous researchers. Herein, oxygen-defective vanadium oxide nanodots (VOx NDs) with ultra-small size and great dispersibility were synthesized via a novel user-friendly method, and then doxorubicin was loaded onto the VOx NDs surfaces. The VOx NDs had great photothermal conversion efficiency and stability. Doxorubicin-loaded VOx NDs can simultaneously serve as therapeutic agent and tumor microenvironment-activable HSP60 inhibitor, resulting in improved efficacy of photothermal therapy and released active doxorubicin for chemotherapy. Finally, we show that synergistic treatment achieved significant therapeutic effects in mice. These results provided a promising strategy for developing novel methods of synthesizing metal oxide semiconductors for enhanced synergistic cancer treatment.

Artemisinin-Loaded Mesoporous Nanoplatform for pH-Responsive Radical Generation Synergistic Tumor Theranostics.

The development of novel and effective cancer treatments will greatly contribute to prolonging and improving patient lives. In this study, a multifunctional nanoplatform was designed and developed based on mesoporous NiO (mNiO) nanoparticles and terbium complexes as an artemisinin (ART) vehicle, a T2-weighted contrast agent, and a luminescence imaging probe. mNiO is a novel pH-responsive material that can degrade and release nickel ions (Ni2+) in an acidic tumor microenvironment. The endoperoxide bridge bond in the structure of ART tends to react with Ni2+ to produce radicals that can kill tumor cells. On the basis of its excellent near-infrared absorbance, mNiO can also be considered as a novel photothermal conversion agent for cancer photothermal therapy (PTT). Compared with free ART or PTT only, this novel agent showed remarkably enhanced antitumor activity in cultured cells and in tumor mice models, owing to the hypoxic tumor microenvironment impelling synergistic therapeutic action. These results provide a novel way of using a promising natural drug-based nanoplatform for synergistic therapy of tumors.

Ultra-small pH-responsive Nd-doped NaDyF4 Nanoagents for Enhanced Cancer Theranostic by in situ Aggregation.

To achieve accurate tumor location and highly efficient cancer therapy effect, the properties of cancer theranostic agents should be optimized and enhanced. In this work, ultra-small Nd doped NaDyF4 were firstly reported as novel contrast agents for near-infrared second window downconversion luminescence (NIR II DCL) and magnetic resonance imaging. Based on the optimization strategy, gallic acid-Fe(III) complex modified NaDyF4:10%Nd (NaDyF4:10%Nd-GA-Fe) was selected as the optimal agent with high transversal relaxivity, strong NIR II DCL, high photothermal conversion efficiency, and low toxicity. In vitro experiment found that it can be aggregated rapidly in low pH condition, leading to the particle size increasing. Due to the theranostic properties coupled in NaDyF4:10%Nd-GA-Fe are size dependent, properties enhancement was observed within the pH responsive aggregation progress. Further study in small animal model bearing tumor demonstrated the enhanced cancer theranostic by in situ aggregation. The optimized nanoagents have potential applications in medical and also provide a novel strategy for future study of cancer theranostic enhancement.