Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy.

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy.

OBJECTIVE: To investigate the efficacy of 125I seed brachytherapy for non-central pelvic recurrence of cervical cancer after external beam radiotherapy, and to analyze the clinical influential factors. METHODS: Between June 2015 and April 2022, 32 patients with 41 lesions were treated with 125I seed brachytherapy. The seeds were implanted under the guidance of CT and/or 3D-printed template images at a median dose of 100 Gy (range, 80-120 Gy), and the local control rate (LCR) and survival rates were calculated. We used multivariate logistic regression to identify prognosis predictors, and receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off values. RESULTS: The median follow-up was 48.52 months (range, 4-86 months), and the 6-, 12-, and 24-month LCR was 88.0%, 63.2%, and 42.1%, respectively. The 1- and 2-year survival rates were 36% and 33%, respectively, and the median survival time was 13.26 months. No significant adverse events occurred. Multivariate regression analysis showed that tumor diameter, tumor stage, and LCR were independent factors influencing survival. ROC curve analysis showed that the area under the curve for tumor diameter and D90 were 0.765 and 0.542, respectively, with cut-off values of 5.3 cm and 108.5 Gy. CONCLUSIONS: The present findings indicate that 125I seed brachytherapy is feasible for treating non-central pelvic recurrence of cervical cancer after external beam radiotherapy. Further, tumor diameter < 5.3 cm and immediate postoperative D90 > 108.5 Gy were associated with better efficacy.

Light-field photography using differential high-speed aperture coding.

Programmable aperture light-field photography enables the acquisition of angular information without compromising spatial resolution. However, direct current (DC) background noise is unavoidable in images recorded by programmable aperture light-field photography, leading to reducing the contrast of reconstructed images. In addition, it requires sacrificing temporal resolution to obtain angular information, making it a challenge to capture dynamic scenes. In this paper, we propose programmable aperture light-field photography using differential high-speed aperture coding. This method effectively reduces DC noise and produces high-contrast refocused images. Furthermore, we build a light-field camera based on a 1250 Hz spatial light modulator and a 1250 fps high-speed camera, achieving dynamic light-field photography at 1110(H)×800(V) resolution and 24 fps. Our results demonstrate significant improvements in image contrast and exhibit considerable promise for diverse applications.

Melanin Nanoparticle-Modified Probiotics for Targeted Synergistic Therapy of Ulcerative Colitis.

Ulcerative colitis (UC) is a recurrent chronic mucosal inflammation disease whose most significant pathological characteristics are intestinal inflammation and damaged mucosal barrier induced by reactive oxygen/nitrogen species, abnormal immune microenvironment, and intestinal microecological imbalance. Oral probiotics are a living therapy for intestinal diseases, but their clinical application is hindered by poor bacterial biological activity and insufficient intestinal retention. Here, we developed a targeted oral formulation, functionalized probiotic Lf@MPB, with Lactobacillus fermentum (Lf) as the core and modified melanin nanoparticles (MNPs) on its surface through a click reaction of tricarboxyphenylboronic acid for synergistic therapy of UC. In vitro experiments showed that Lf@MPB not only possessed strong free radical scavenging ability, reduced cellular mitochondrial polarization, and inhibited apoptosis but also significantly enhanced the viability of Lf probiotics in simulated gastrointestinal fluid. Fluorescence imaging in vivo revealed the high accumulation of Lf@MPB at the site of intestinal inflammation in dextran sulfate sodium-induced UC mice. Moreover, in vivo results demonstrated that Lf@MPB effectively alleviated oxidative stress and inflammatory response and restored the intestinal barrier. In addition, 16S rRNA gene sequencing verified that Lf@MPB could increase the abundance and diversity of intestinal microbial communities and optimize microbial composition to inhibit the progression of UC. This work combines effective antioxidant and anti-inflammatory strategies with the oral administration of functionalized probiotics to provide a promising alternative for UC treatment.

Serum mir-142-3p release in children with viral encephalitis and its relationship with nerve injury and inflammatory response.

BACKGROUND: Viral encephalitis (VE) is a common infectious disease of the central nervous system in children. Children with severe disease may have progressive neurological damage and even lead to death. AIMS: To assess the serum miR-142-3p levels in children with VE and the correlation between miR-142-3p and the severity and prognosis of VE. Besides, its relationship with nerve injury and inflammatory response was assessed. METHODS: Children with VE were regarded as a case group and healthy children served as control. The content of serum miR-142-3p was determined using real-time quantitative PCR. The risk factors associated with severity and prognosis of cases were evaluated using logistic analysis. The discrepancy in miR-142-3p levels, nerve injury-related indicators, and inflammatory cytokines were contrasted among groups. The ROC curve was conducted to assess the diagnostic performance of serum miR-142-3p in predicting prognosis of children with VE. RESULTS: The altered expression of miR-142-3p in serum of children with VE was enhanced in contrast to healthy control. Serum nerve injury indicators MBP, ß-EP, and NSE levels and serum inflammatory cytokines IL-6, IL-18, and IFN-γ were high in children with VE in contrast to healthy control, and had positive relevance with serum miR-142-3p. Besides, serum miR-142-3p was a risk factor associated with the severity and prognosis of children with VE. Serum miR-142-3p had diagnostic performance in predicting the prognosis of children with VE. CONCLUSION: Serum miR-142-3p content is high in children with VE and maybe a diagnosis marker for predicting prognosis. The specific miR-142-3p expression may be directly related to the severity of nerve injury and inflammatory response for VE.

Ubiquitin ligase TRIM22 inhibits ovarian cancer malignancy via TCF4 degradation.

Ovarian cancer (OC) is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in OC. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in OC. TRIM22 protein and mRNA levels were analyzed in samples from both clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, co-immunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in OC tissues. Furthermore, upregulation of TRIM22 significantly inhibited OC cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in OC cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in OC is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of OC.

Development and Validation of a Novel Prognostic Nomogram Based on Platelet and CD8+T Cell Counts in Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis.

Purpose: Portal vein tumor thrombosis (PVTT) is one of the hallmarks of advanced Hepatocellular carcinoma (HCC). Platelet (PLT) function parameters and CD8+T cells (CD8+Ts) play an important role in HCC progression and metastasis. This study is committed to establishing an efficient prognosis prediction model and exploring the combined effect of PLT and CD8+Ts on PVTT prognosis. Patients and Methods: This retrospective study collected 932 HCC patients with PVTT from 2007 to 2017 and randomly divided them into a training cohort (n = 656) and a validation cohort (n = 276). We performed multivariable Cox and Elastic-net regression analysis, constructed a nomogram and used Kaplan-Meier survival curves to compare overall survival and progression-free survival rates in different substrata. Relationships between indicators involved were also analyzed. Results: We found tumor number, size, treatment, PLT, γ-glutamyl transferase, alpha-fetoprotein, mean platelet volume, and CD8+Ts were related to the 5-year OS of patients with PVTT, and established a nomogram. The area under the receiver operating characteristic curve (AUCs) for predicting the 1-year OS rates were 0.767 and 0.794 in training and validation cohorts. The calibration curve and decision curve indicated its predictive consistency and strong clinical utility. We also found those with low PLT (<100*10^9/L) and high CD8+Ts (>320 cells/µL) had a better prognosis. Conclusion: We established a well-performing prognostic model for PVTT based on platelet functional parameters and CD8+Ts, and found that PT-8 formed by PLT and CD8+Ts was an excellent predictor of the prognosis of PVTT.

Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis.

Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.

Integrating Network Pharmacology and Experimental Validation to Decipher the Mechanism of Action of Astragalus-Atractylodes Herb Pair in Treating Hepatocellular Carcinoma.

Purpose: Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), Astragalus (Latin name: Hedysarum Multijugum Maxim; Chinese name: Huangqi, HQ) and Atractylodes (Latin name: Atractylodes Macrocephala Koidz; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment. Methods: The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments. Results: Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8+T cells, inhibit CD8+T cell exhaustion and restore the function of exhausted CD8+T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8+T cells. Conclusion: This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8+T cells.

Intracellular magnetic hyperthermia reverses sorafenib resistance in hepatocellular carcinoma through its action on signaling pathways.

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), unfortunately encounters resistance in most patients, leading to disease progression. Traditional approaches to counteract this resistance, particularly those targeting the RAF-MEK-ERK pathway, often face clinical feasibility limitations. Magnetic hyperthermia (MH), unlike conventional thermal therapies, emerges as a promising alternative. It uniquely combines magnetothermal effects with an increase in reactive oxygen species (ROS). This study found the potential of intracellular MH enhanced the efficacy of sorafenib, increased cellular sensitivity to sorafenib, and reversed sorafenib resistance by inhibiting the RAF-MEK-ERK pathway in an ROS-dependent manner in a sorafenib-resistant HCC cell. Further, in a sorafenib-resistant HCC mouse model, MH significantly sensitized tumors to sorafenib therapy, resulting in inhibited tumor growth and improved survival rates. This presents a promising strategy to overcome sorafenib resistance in HCC, potentially enhancing therapeutic outcomes for patients with this challenging condition.

Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex.

BACKGROUND: Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions. METHODS: Skeletal muscles from 2-month-old SPEG-deficient (Speg-CKO) and wild-type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings. RESULTS: We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg-CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction (P < 1e-15) and peroxisome proliferator-activated receptor signalling (P < 9e-14). CONCLUSIONS: We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG-interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi-omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

Outer membrane vesicle-wrapped manganese nanoreactor for augmenting cancer metalloimmunotherapy through hypoxia attenuation and immune stimulation.

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO2@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H2O2 into O2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8+T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. STATEMENT OF SIGNIFICANCE: A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H2O2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8+T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

Investigation on the exopolysaccharide production from blueberry juice fermented with lactic acid bacteria: Optimization, fermentation characteristics and Vis-NIR spectral model.

The exopolysaccharide production from blueberry juice fermented were investigated. The highest exopolysaccharide yield of 2.2 ± 0.1 g/L (increase by 32.5 %) was reached under the conditions of temperature 26.5 °C, pH 5.5, inoculated quantity 5.4 %, and glucose addition 9.1 % using the artificial neural network and genetic algorithm. Under the optimal conditions, the viable cell counts and total acids were increased by 2.0 log CFU/mL and 1.6 times, respectively, while the content of phenolics and anthocyanin was decreased by 9.26 % and 7.86 %, respectively. The changes of these components affected the exopolysaccharide biosynthesis. The absorption bands of -OH and -CH associated with the main functional groups of exopolysaccharide were detected by Visible near-infrared spectroscopy. The prediction model based on spectrum results was constructed. Competitive adaptive reweighted sampling and the random forest were used to enhance the model's prediction performance with the value of RC = 0.936 and RP = 0.835, indicating a good predictability of exopolysaccharides content during fermentation.

BOLD: Blood-gas and Oximetry Linked Dataset.

Pulse oximeters measure peripheral arterial oxygen saturation (SpO2) noninvasively, while the gold standard (SaO2) involves arterial blood gas measurement. There are known racial and ethnic disparities in their performance. BOLD is a dataset that aims to underscore the importance of addressing biases in pulse oximetry accuracy, which disproportionately affect darker-skinned patients. The dataset was created by harmonizing three Electronic Health Record databases (MIMIC-III, MIMIC-IV, eICU-CRD) comprising Intensive Care Unit stays of US patients. Paired SpO2 and SaO2 measurements were time-aligned and combined with various other sociodemographic and parameters to provide a detailed representation of each patient. BOLD includes 49,099 paired measurements, within a 5-minute window and with oxygen saturation levels between 70-100%. Minority racial and ethnic groups account for ~25% of the data - a proportion seldom achieved in previous studies. The codebase is publicly available. Given the prevalent use of pulse oximeters in the hospital and at home, we hope that BOLD will be leveraged to develop debiasing algorithms that can result in more equitable healthcare solutions.

Comparison of the effects of Amomum tsaoko and its adulterants on functional dyspepsia rats based on metabolomics analysis.

Amomum tsaoko (AT) is commonly used in clinical practice to treat abdominal distension and pain. It is also a seasoning for cooking, with the functions of appetizing, invigorating the spleen, and being digestive-promoting. Amomum tsaoko (AT) has three adulterants, Amomum paratsaoko (AP), Amomum koenigii (AK), and Alpinia katsumadai Hayata, because of the confusion in historical classics regarding recorded sources as well as the near geographic distribution and fruit morphological similarities. In this study, we established a functional dyspepsia (FD) rat model and then treated it with the corresponding medicinal solutions AT, AP, AK, and AKH. The gastric emptying rate, intestinal propulsion rate, serum biochemical indicators, histopathological changes, and fecal metabolism were measured. The efficacy and mechanism of AT, AP, AK, and AKH in the treatment of FD were compared. Fecal metabolomics revealed that 20 potential biomarkers were involved in seven significant metabolic pathways in FD rats. These pathways include ubiquinone and other terpenoid-quinone biosynthesis, glycerophospholipid metabolism, tyrosine metabolism, primary bile acid biosynthesis, purine metabolism, folate biosynthesis, and amino sugar and nucleotide sugar metabolism. AP regulates 6 metabolic pathways, 5 metabolic pathways affected by AT, 4 metabolic pathways affected by AK, and 2 metabolic pathways affected by AKH.The above results suggest that the different effects of AT, AP, AK, and AKH on FD rats may be due to their different regulatory effects on the metabolome.

Carbon monoxide-induced autophagy enhances human mesenchymal stromal cell function via paracrine actions in murine polymicrobial sepsis.

Sepsis is a life-threatening process due to organ dysfunction resulting from severe infections. Mesenchymal stromal cells (MSCs) are being investigated as therapy for sepsis, along with conditioning regimens to improve their function. Carbon monoxide (CO) gas, which is cytoprotective at low doses, induces autophagy and is a mediator of inflammation. We evaluated CO-induced autophagy in human MSCs (hMSCs), and its impact on cell function in murine cecal ligation and puncture. Conditioning of hMSCs with CO ex vivo resulted in enhanced survival and bacterial clearance in vivo, and neutrophil phagocytosis of bacteria in vitro. Decreased neutrophil infiltration and less parenchymal cell death in organs were associated with increased macrophage efferocytosis of apoptotic neutrophils, promoting resolution of inflammation. These CO effects were lost when the cells were exposed to autophagy inhibition prior to gas exposure. When assessing paracrine actions of CO-induced autophagy, extracellular vesicles (EVs) were predominantly responsible. CO had no effect on EV production, but altered their miRNA cargo. Increased expression of miR-145-3p and miR-193a-3p by CO was blunted with disruption of autophagy, and inhibitors of these miRNAs led to a loss of neutrophil phagocytosis and macrophage efferocytosis. Collectively, CO-induced autophagy enhanced hMSC function during sepsis via paracrine actions of MSC-derived EVs.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Chitosan- and hyaluronic acid-based nanoarchitectures in phototherapy: Combination cancer chemotherapy, immunotherapy and gene therapy.

Cancer phototherapy has introduced a new potential modality for tumor suppression. However, the efficacy of phototherapy has been limited due to a lack of targeted delivery of photosensitizers. Therefore, the application of biocompatible and multifunctional nanoparticles in phototherapy is appreciated. Chitosan (CS) as a cationic polymer and hyaluronic acid (HA) as a CD44-targeting agent are two widely utilized polymers in nanoparticle synthesis and functionalization. The current review focuses on the application of HA and CS nanostructures in cancer phototherapy. These nanocarriers can be used in phototherapy to induce hyperthermia and singlet oxygen generation for tumor ablation. CS and HA can be used for the synthesis of nanostructures, or they can functionalize other kinds of nanostructures used for phototherapy, such as gold nanorods. The HA and CS nanostructures can combine chemotherapy or immunotherapy with phototherapy to augment tumor suppression. Moreover, the CS nanostructures can be functionalized with HA for specific cancer phototherapy. The CS and HA nanostructures promote the cellular uptake of genes and photosensitizers to facilitate gene therapy and phototherapy. Such nanostructures specifically stimulate phototherapy at the tumor site, with particle toxic impacts on normal cells. Moreover, CS and HA nanostructures demonstrate high biocompatibility for further clinical applications.

MP-3 microperimeter in early primary open angle glaucoma with a new pattern.

AIM: To investigate macular microperimetry in patients with early primary open angle glaucoma (POAG) using a new custom-made pattern, and analyze the characteristics of macular sensitivity. METHODS: This case-control study included 38 patients with POAG, who were divided into pre-perimetric glaucoma (18 eyes of 18 patients), early-stage (20 eyes of 20 patients), and control (20 eyes of 20 patients) groups. All subjects underwent standard 24-2 humphrey visual field test. An MP-3 microperimeter with a new custom-made pattern (28 testing points distributed in four quadrants, covering the central 10° of the retina) was used to evaluate macular sensitivity. Ganglion cell complex (GCC) thicknesses were examined using an RS-3000 Advance OCT system. The features of structure and function were analysed per quadrant. RESULTS: The pre-perimetric glaucoma group had significantly lower inferior hemifield macular sensitivity compared to controls (P<0.05). The early-stage POAG group had significantly lower average, inferior hemifield, inferonasal, and inferotemporal mean sensitivities compared to the pre-perimetric glaucoma group (P<0.05), and lower macular sensitivity in all sectors compared to controls (P<0.05). Regarding GCC thickness, all sectors in the early-stage POAG group became thinner compared to those in controls (P<0.05); whereas all sectors in the early-stage POAG group, except the superonasal quadrant, became thinner compared to those in the pre-perimetric glaucoma group (P<0.05). Macular sensitivity and GCC thickness were significantly associated in each sector. The inferotemporal quadrant had the highest correlation coefficients (0.840). The structure-function relationship for the inferonasal and inferotemporal sectors was stronger compared to the corresponding superior sectors. CONCLUSION: Microperimetry reveals variations in macular sensitivity in patients with early glaucoma earlier than conventional perimetry, particularly in pre-perimetric glaucoma cases in which it might be undetectable by conventional methods. The new custom-made pattern may improve the accuracy of microperimetry by enhancing point arrangement and reducing fatigue effects. Macular sensitivity measured by MP-3 with this pattern shows statistically significant structural and functional associations with the thicknesses of the GCC.

Integrated time-series biochemical, transcriptomic, and metabolomic analyses reveal key metabolites and signaling pathways in the liver of the Chinese soft-shelled turtle (Pelodiscus sinensis) against Aeromonas hydrophila infection.

Introduction: Aeromonas hydrophila, a bacterium widely distributed in the natural environment, causes multiple diseases in various animals. Exploring the mechanism of the host defense against A. hydrophila can help develop efficient strategies against Aeromonas infection. Methods: Herein, we investigated the temporal influence of A. hydrophila on the Chinese soft-shelled turtle, an economically important species, at the biochemical, transcriptomic, and metabolomic levels. Plasma parameters were detected with the test kits. Transcriptome and metabolome were respectively applied to screen the differentially expressed genes and metabolites. Results: The contents or activities of these plasma parameters were significantly increased at 24 hpi and declined at 96 hpi, indicating that 24 and 96 hpi were two important time points during infection. Totals of 3121 and 274 differentially expressed genes (DEGs) from the transcriptome while 74 and 91 differentially abundant metabolites (DAMs) from the metabolome were detected at 24 and 96 hpi. The top DEGs at 24 hpi included Ccl2, Ccl3, Ccl4, Il1ß, Il6, Il7, Il15, Tnf, and Tnfr1 while Zap70, Cd3g, Cd8a, Itk, Pik3r3, Cd247, Malt1, and Cd4 were the most abundant at 96 hpi. The predominant DAMs included O-phospho-L-serine, γ-Aminobutyric acid, orotate, L-tyrosine, and L-tryptophan at 24 hpi, as well as L-glutamic acid, L-arginine, glutathione, glutathione disulfide, and citric acid at 96 hpi. Discussion: The combined analysis of DEGs and DAMs revealed that tryptophan metabolism, nicotinate and nicotinamide metabolism, as well as starch and sucrose metabolism, were the most important signaling pathways at the early infective stage while tyrosine metabolism, pyrimidine metabolism, as well as alanine, aspartate and glutamate metabolism were the most crucial pathways at the later stage. In general, our results indicated that the Chinese soft-shelled turtle displays stage-specific physiological responses to resist A. hydrophila infection.