Histology, fatty acid composition, antioxidant and glycolipid metabolism, and transcriptome analyses of the acute cold stress response in Phoxinus lagowskii.

Water temperature is a crucial environmental factor that significantly affects the physiological and biochemical processes of fish. Due to the occurrence of cold events in aquaculture, it is imperative to investigate how fish respond to cold stress. This study aims to uncover the mechanisms responds to acute cold stress by conducting a comprehensive analysis of the histomorphology, glycolipid metabolic and antioxidant enzymes, fatty acid composition and transcriptome at three temperatures (16 °C, 10 °C and 4 °C) in Phoxinus lagowskii. Our results showed that cold stress not damaged muscle microstructure but caused autophagy (at 10 °C). In addition, serum glucose (Glu) and triglycerides (TG) increased during cold stress. The activities of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), fructose phosphokinase (PFK), hexokinase (HK), pyruvate kinase (PK), and malondialdehyde (MDA) content in muscle were measured and analyzed. During cold stress, superoxide dismutase and catalase activities increased, reactive oxygen species content decreased. No significant difference in Glutathione peroxidase (GPx) activity, malondialdehyde and total cholesterol (T-CHO) contents among groups. Phosphokinase and pyruvate kinase activities decreased, and HK activity increased during cold stress. Our study resulted in the identification of a total of 25,400 genes, with 2524 genes showing differential expression across different temperature treatments. Furthermore, KEGG pathway indicated that some pathways upregulated during light cold stress (at 10 °C, including autophagy, and AMP-activated protein kinase (AMPK) signaling pathway. Additionally, circadian rhythm is among the most enriched pathways in genes up-regulated during severe cold stress (at 4 °C). Our findings offer valuable insights into how cold-water fish respond to cold stress.

Mechanically strained osteocyte-derived exosomes contained miR-3110-5p and miR-3058-3p and promoted osteoblastic differentiation.

BACKGROUND: Osteocytes are critical mechanosensory cells in bone, and mechanically stimulated osteocytes produce exosomes that can induce osteogenesis. MicroRNAs (miRNAs) are important constituents of exosomes, and some miRNAs in osteocytes regulate osteogenic differentiation; previous studies have indicated that some differentially expressed miRNAs in mechanically strained osteocytes likely influence osteoblastic differentiation. Therefore, screening and selection of miRNAs that regulate osteogenic differentiation in exosomes of mechanically stimulated osteocytes are important. RESULTS: A mechanical tensile strain of 2500 µÎµ at 0.5 Hz 1 h per day for 3 days, elevated prostaglandin E2 (PGE2) and insulin-like growth factor-1 (IGF-1) levels and nitric oxide synthase (NOS) activity of MLO-Y4 osteocytes, and promoted osteogenic differentiation of MC3T3-E1 osteoblasts. Fourteen miRNAs differentially expressed only in MLO-Y4 osteocytes which were stimulated with mechanical tensile strain, were screened, and the miRNAs related to osteogenesis were identified. Four differentially expressed miRNAs (miR-1930-3p, miR-3110-5p, miR-3090-3p, and miR-3058-3p) were found only in mechanically strained osteocytes, and the four miRNAs, eight targeted mRNAs which were differentially expressed only in mechanically strained osteoblasts, were also identified. In addition, the mechanically strained osteocyte-derived exosomes promoted the osteoblastic differentiation of MC3T3-E1 cells in vitro, the exosomes were internalized by osteoblasts, and the up-regulated miR-3110-5p and miR-3058-3p in mechanically strained osteocytes, were both increased in the exosomes, which was verified via reverse transcription quantitative polymerase chain reaction (RT-qPCR). CONCLUSIONS: In osteocytes, a mechanical tensile strain of 2500 µÎµ at 0.5 Hz induced the fourteen differentially expressed miRNAs which probably were in exosomes of osteocytes and involved in osteogenesis. The mechanically strained osteocyte-derived exosomes which contained increased miR-3110-5p and miR-3058-3p (two of the 14 miRNAs), promoted osteoblastic differentiation.

PAD4 Inhibitor-Functionalized Layered Double Hydroxide Nanosheets for Synergistic Sonodynamic Therapy/Immunotherapy Of Tumor Metastasis.

Sonodynamic therapy (SDT) is demonstrated to trigger the systemic immune response of the organism and facilitate the treatment of metastatic tumors. However, SDT-mediated neutrophil extracellular traps (NETs) formation can promote tumor cell spread, thus weakening the therapeutic effectiveness of metastatic tumors. Herein, the amorphous CoW-layered double hydroxide (a-CoW-LDH) nanosheets are functionalized with a peptidyl arginine deiminase 4 (PAD4) inhibitor, i.e., YW3-56, to construct a multifunctional nanoagent (a-LDH@356) for synergistic SDT/immunotherapy. Specifically, a-CoW-LDH nanosheets can act as a sonosensitizer to generate abundant reactive oxygen species (ROS) under US irradiation. After loading with YW3-56, a-LDH@356 plus US irradiation not only effectively induces ROS generation and immunogenic cell death, but also inhibits the elevation of citrullinated histone H3 (H3cit) and the release of NETs, enabling a synergistic enhancement of anti-tumor metastasis effect. Using 4T1 tumor model, it is demonstrated that combining a-CoW-LDH with YW3-56 stimulates an anti-tumor response by upregulating the proportion of immune-activated cells and inducing polarization of M1 macrophages, and inhibits immune escape by downregulating the expression of PD-1 on immune cells under US irradiation, which not only arrests primary tumor progression with a tumor inhibition rate of 69.5% but also prevents tumor metastasis with the least number of lung metastatic nodules.

MIDRC-MetricTree: a decision tree-based tool for recommending performance metrics in artificial intelligence-assisted medical image analysis.

Purpose: The Medical Imaging and Data Resource Center (MIDRC) was created to facilitate medical imaging machine learning (ML) research for tasks including early detection, diagnosis, prognosis, and assessment of treatment response related to the coronavirus disease 2019 pandemic and beyond. The purpose of this work was to create a publicly available metrology resource to assist researchers in evaluating the performance of their medical image analysis ML algorithms. Approach: An interactive decision tree, called MIDRC-MetricTree, has been developed, organized by the type of task that the ML algorithm was trained to perform. The criteria for this decision tree were that (1) users can select information such as the type of task, the nature of the reference standard, and the type of the algorithm output and (2) based on the user input, recommendations are provided regarding appropriate performance evaluation approaches and metrics, including literature references and, when possible, links to publicly available software/code as well as short tutorial videos. Results: Five types of tasks were identified for the decision tree: (a) classification, (b) detection/localization, (c) segmentation, (d) time-to-event (TTE) analysis, and (e) estimation. As an example, the classification branch of the decision tree includes two-class (binary) and multiclass classification tasks and provides suggestions for methods, metrics, software/code recommendations, and literature references for situations where the algorithm produces either binary or non-binary (e.g., continuous) output and for reference standards with negligible or non-negligible variability and unreliability. Conclusions: The publicly available decision tree is a resource to assist researchers in conducting task-specific performance evaluations, including classification, detection/localization, segmentation, TTE, and estimation tasks.

Identifying the unmet needs of post-treatment colorectal cancer survivors: A critical literature review.

PURPOSE: Following treatment completion, colorectal cancer (CRC) survivors experience various unmet needs. This review aims to synthesize the unmet needs of CRC survivors after treatment and to identify demographic, disease or treatment-related, healthcare-related, and psychosocial factors correlated with unmet needs. METHOD: English or Chinese articles that focused on CRC survivors' post-treatment unmet needs were systematically searched from the five electronic databases, which included CINAHL, PubMed, Embase, PsycINFO, and the China Academic Journal Full-text Database, from the launch of databases to July 2023. The reference lists of the subsequent articles were further screened. RESULTS: 136 individual needs extracted from 50 manuscripts were classified into nine domains based on the Supportive Care Framework. The top four unmet needs identified by CRC survivors were assistance with fears of cancer recurrence, information about managing illness and side effects at home, emotional or psychological support and reassurance, and help with sexuality problems. Following surgery, CRC survivors showed strong demand in the physical, psychological, and information domains. Survivors completed treatment within 1-year had more diverse needs than those who completed 1-3 years. Unmet needs may be greater among CRC survivors who were young, female, more educated, and unmarried. Furthermore, greater unmet needs were associated with distress, anxiety, depression, and worse quality of life. CONCLUSIONS: Despite diverse needs experienced by post-treatment CRC survivors, a predominant focus on fears of cancer recurrence, information, psychological support, and sexuality needs is noted. Future studies should further explore the needs of CRC survivors after specific treatment and in different post-treatment periods.

Turning Polysaccharides into Injectable and Rapid Self-Healing Antibacterial Hydrogels for Antibacterial Treatment and Bacterial-Infected Wound Healing.

Great efforts have been devoted to the development of novel and multifunctional wound dressing materials to meet the different needs of wound healing. Herein, we covalently grafted quaternary ammonium groups (QAGs) containing 12-carbon straight-chain alkanes to the dextran polymer skeleton. We then oxidized the resulting product into oxidized quaternized dextran (OQD). The obtained OQD polymer is rich in antibacterial QAGs and aldehyde groups. It can react with glycol chitosan (GC) via the Schiff-base reaction to form a multifunctional GC@OQD hydrogel with good self-healing behavior, hemostasis, injectability, inherent superior antibacterial activity, biocompatibility, and excellent promotion of healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. The biosafe and nontoxic GC@OQD hydrogel with a three-dimensional porous network structure possesses an excellent swelling rate and water retention capacity. It can be used for hemostasis and treating irregular wounds. The designed GC@OQD hydrogel with inherent antibacterial activity possesses good antibacterial efficacy on both S. aureus (Gram-positive bacteria) and Escherichia coli (Gram-negative bacteria), as well as MRSA bacteria, with antibacterial activity greater than 99%. It can be used for the treatment of wounds infected by MRSA and significantly promotes the healing of wounds. Thus, the multifunctional antibacterial GC@OQD hydrogel has the potential to be applied in clinical practice as a wound dressing.

New Insights into Aggregation Behaviors of the UV-Irradiated Dissolved Biochars (DBioCs) in Aqueous Environments: Effects of Water Chemistries and Variation in the Hamaker Constant.

The aggregation behavior of ubiquitous dissolved black carbon (DBC) largely affects the fate and transport of its own contaminants and the attached contaminants. However, the photoaging processes and resulting effects on its colloidal stability remain yet unknown. Herein, dissolved biochars (DBioCs) were extracted from common wheat straw biochar as a proxy for an anthropogenic DBC. The influences of UV radiation on their aggregation kinetics were systematically investigated under various water chemistries (pH, electrolytes, and protein). The environmental stability of the DBioCs before and after radiation was further verified in two natural water samples. Hamaker constants of pristine and photoaged DBioCs were derived according to Derjaguin-Landau-Verwey-Overbeek (DLVO) prediction, and its attenuation (3.19 ± 0.15 × 10-21 J to 1.55 ± 0.07 × 10-21 J after 7 days of radiation) was described with decay kinetic models. Pearson correlation analysis revealed that the surface properties and aggregation behaviors of DBioCs were significantly correlated with radiation time (p < 0.05), indicating its profound effects. Based on characterization and experimental results, we proposed a three-stage mechanism (contended by photodecarboxylation, photo-oxidation, and mineral exposure) that DBioCs might experience under UV radiation. These findings would provide an important reference for potential phototransformation processes and relevant behavioral changes that DBC may encounter.

A MgAl-LDH-CuS nanosheet-based thermo-responsive composite hydrogel with nir-responsive angiogenesis inhibitor releasing capability for multimode starvation therapy.

The rapid proliferation of tumors is highly dependent on the nutrition supply of blood vessels. Cutting off the nutrient supply to tumors is an effective strategy for cancer treatment, known as starvation therapy. Although various hydrogel-based biomaterials have been developed for starvation therapy through glucose consumption or intravascular embolization, the limitations of single-mode starvation therapy hinder their therapeutic effects. Herein, we propose a dual-function nutrition deprivation strategy that can block the nutrients delivery through extravascular gelation shrinkage and inhibit neovascularization through angiogenesis inhibitors based on a novel NIR-responsive nanocomposite hydrogel. CuS nanodots-modified MgAl-LDH nanosheets loaded with angiogenesis inhibitor (sorafenib, SOR) are incorporated into the poly(n-isopropylacrylamide) (PNIPAAm) hydrogel by radical polymerization to obtain the composite hydrogel (SOR@LDH-CuS/P). The SOR@LDH-CuS/P hydrogel can deliver hydrophobic SOR with a NIR-responsive release behavior, which could decrease the tumor vascular density and accelerate cancer cells apoptosis. Moreover, the SOR@LDH-CuS/P hydrogel exhibits higher (3.5 times) compressive strength than that of the PNIPAAm, which could squeeze blood vessels through extravascular gelation shrinkage. In vitro and in vivo assays demonstrate that the interruption of nutrient supply by gelation shrinkage and the prevention of angiogenesis by SOR is a promising strategy to inhibit tumor growth for multimode starvation therapy.

Characteristics of cervicovaginal microflora at different cervical maturity during late pregnancy: A nested case-control study.

OBJECTIVE: The mechanism of cervical ripening in late pregnancy is still unclear. The vaginal microbiome has been reported to correlate with the preterm birth and short cervix in pregnant women. However, the associations between the cervical maturity and the vaginal microbiome are still poorly understood. We aim to analyze the cervicovaginal microflora in women with ripe cervix and in those who are unripe when delivering at term. METHODS: Cervicovaginal swabs were collected between 40 and 41 weeks of gestation from the following 2 different groups of patients: ripe group (n = 25) and unripe group (n = 25). Samples were tested using 16S ribosomal RNA gene high-throughput sequencing and analyzed by bioinformatics platform. RESULTS: This study highlights the relationship between cervical maturity during late pregnancy and the composition of the cervicovaginal microflora. Both α- and ß-diversity analyses demonstrated significant differences between women with a ripe cervix and those with an unripe cervix. Notably, the Lactobacillus profile was found to be closely linked to cervical maturity. There was a significant difference in the vaginal community state type, with CST IV being more prevalent in women with an unripe cervix. Furthermore, the association between CST IV and the unripe cervix group, as indicated by the odds ratio of 8.6, underscores its relevance in evaluating cervical maturity, when compared to other Lactobacillus-dominant community state types. Additionally, several bacterial taxa, particularly Lactobacillus, exhibited differential relative abundances between the two groups. CONCLUSION: This study provided significant evidence regarding the relationship between the vaginal microbiome and cervical maturity, highlighting the differential diversity, community state types, and specific bacterial taxa, such as Lactobacillus, that are associated with cervical maturation status. These findings contributed to our understanding of the dynamics of the cervicovaginal microflora during late pregnancy and its implications for cervical health.

LDLR c.415G > A causes familial hypercholesterolemia by weakening LDLR binding to LDL.

BACKGROUND: Familial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in low-density lipoprotein receptor (LDLR), an FH-related gene, is a pathogenic variant in FH by in silico analysis and functional experiments. METHODS: The proband and his family were evaluated using the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related variants. In silico analyses were used to evaluate the pathogenicity of the candidate variant and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A variant in vitro. RESULTS: Four of six participants had a diagnosis of FH. It was estimated that the LDLR c.415G > A variant in this family was likely pathogenic. Western blotting and qPCR suggested that LDLR c.415G > A does not affect protein expression. Functional studies showed that this variant may lead to dyslipidemia by impairing the binding and absorption of LDLR to low-density lipoprotein ( LDL). CONCLUSION: LDLR c.415G > A is a pathogenic variant in FH; it causes a significant reduction in LDLR's capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of variants associated with FH.

FHND004 inhibits malignant proliferation of multiple myeloma by targeting PDZ-binding kinase in MAPK pathway.

Inhibitors of Epidermal growth factor receptor tyrosine kinase (EGFR-TKIs) are producing impressive benefits to responsive types of cancers but challenged with drug resistances. FHND drugs are newly modified small molecule inhibitors based on the third-generation EGFR-TKI AZD9291 (Osimertinib) that are mainly for targeting the mutant-selective EGFR, particularly for the non-small cell lung cancer (NSCLC). Successful applications of EGFR-TKIs to other cancers are less certain, thus the present pre-clinical study aims to explore the anticancer effect and downstream targets of FHND in multiple myeloma (MM), which is an incurable hematological malignancy and reported to be insensitive to first/second generation EGFR-TKIs (Gefitinib/Afatinib). Cell-based assays revealed that FHND004 and FHND008 significantly inhibited MM cell proliferation and promoted apoptosis. The RNA-seq identified the involvement of the MAPK signaling pathway. The protein chip screened PDZ-binding kinase (PBK) as a potential drug target. The interaction between PBK and FHND004 was verified by molecular docking and microscale thermophoresis (MST) assay with site mutation (N124/D125). Moreover, the public clinical datasets showed high expression of PBK was associated with poor clinical outcomes. PBK overexpression evidently promoted the proliferation of two MM cell lines, whereas the FHND004 treatment significantly inhibited survival of 5TMM3VT cell-derived model mice and growth of patient-derived xenograft (PDX) tumors. The mechanistic study showed that FHND004 downregulated PBK expression, thus mediating ERK1/2 phosphorylation in the MAPK pathway. Our study not only demonstrates PBK as a promising novel target of FHND004 to inhibit MM cell proliferation, but also expands the EGFR kinase-independent direction for developing anti-myeloma therapy.

Study on SH-SY5Y autophagy inhibition and apoptosis induced by methanol extract of Zanthoxylum armatum DC. based on mTOR signal pathway.

Background: Zanthoxylum armatum DC. (ZADC) is a novel food raw material resource, offering both edible and medicinal properties. Recent research has unveiled the toxic nature of ZADC, particularly its close association with the nervous system. In a prior study, we observed that administering methanol extract of Zanthoxylum armatum DC. (MZADC) to rats via gavage at a dose of 1.038 g/kg resulted in various neurotoxicity symptoms, including excessive salivation, reduced mobility, unsteady gait, muscle twitching, and altered respiratory rates. Materials and methods: We conducted cell-based research to assess the safety of ZADC and elucidate its potential toxic mechanism. In addition, we used experimental methods such as Cell Counting Kit-8, Western blot, and Flow cytometry to detect cytotoxicity in SH-SY5Y cells after intervention with MZADC. Results: Following exposure of SY-SY5Y cells with MZADC, a substantial decline in cell viability was observed, accompanied by a concentration-dependent increase in intracellular reactive oxygen species (ROS) levels. Additionally, MZADC induced cellular oxidative stress, leading to elevated malonic dialdehyde (MDA) and superoxide dismutase (SOD) concentrations while decreasing glutathione (GSH) levels. Furthermore, MZADC induced apoptosis at varying doses (20, 40, and 60 µg/mL), and this effect was associated with increased Caspase-3, Bax expressions, and reduced Bcl2 and Bcl2/Bax expressions. In addition, the investigation revealed that MZADC induced autophagy inhibition in SH-SY5Y cells by activating the mTOR signaling pathway, resulting in a decrease in LC3II/LCI and Beclin-1, while increasing p-mTOR/mTOR, p62. Conclusion: Consequently, this study suggests that MZADC triggers the mTOR pathway through oxidative stress in SH-SY5Y cells, ultimately leading to apoptosis. Understanding the toxicity mechanisms associated with ZADC can offer a valuable theoretical and experimental basis for its development and utilization.

Perinatal characteristics and pregnancy outcomes of advanced maternal age women with gestational diabetes mellitus: A retrospective cohort study.

Background and Aims: The prevalence of gestational diabetes mellitus (GDM) continues to increase, and the phenomenon of women giving birth at an older age is becoming more common worldwide. Less is known abouts the impact of GDM combined with advanced maternal age (AMA) on pregnancy outcomes. To explore the impact of AMA complicated with GDM on pregnancy outcomes. Methods: This study included 34,602 pregnancies between 2018 and 2020 in Hangzhou, China. The pregnant women were divided into four groups according to advanced age (≥35 years) and GDM as follows: AMA women without GDM (non-AGDM) group (n = 2614), young pregnant women with GDM (YGDM) group (n = 4016), AMA women with GDM (AGDM) group (n = 850), and young pregnant women without GDM (non-YGDM) group (n = 27,122). Univariate analysis was carried out by Mann-Whitney U test or Pearson's χ 2 test. Multivariate logistic regression analysis was used to investigate the effect of AMA and GDM on pregnancy outcomes. Results: Multivariate logistic regression analysis showed that in the comparison against non-YGDM garoup, the ORs of fetal chromosome abnormality, parity, urgent cesarean section, gravidity, scheduled cesarean section, body mass index (BMI) ≥30 kg/m2, pre-eclampsia, thrombocytopenia, hyperlipidemia, BMI 25-29.9 kg/m2, blood urea nitrogen, fasting blood glucose, and creatinine in AGDM group were 16.044, 4.284, 3.530, 3.284, 3.257, 2.049, 1.935, 1.898, 1.690, 1.471, 1.304, 1.216, and 1.026 (all p < 0.05). Conclusions: The prevalence of pregnant women with AGDM was 2.46% in Hang Zhou, China. The increasing gravidity of AMA women was related to a greater risk of GDM. The AGDM group associated with a greater risks of chromosomal abnormality in offspring and cesarean section, especially urgent cesarean section.

Synergistic Interaction between Metal Single-Atoms and Defective WO3- x Nanosheets for Enhanced Sonodynamic Cancer Therapy.

Although metal single-atom (SA)-based nanomaterials are explored as sonosensitizers for sonodynamic therapy (SDT), they normally exhibit poor activities and need to combine with other therapeutic strategies. Herein, the deposition of metal SAs on oxygen vacancy (OV)-rich WO3- x nanosheets to generate a synergistic effect for efficient SDT is reported. Crystalline WO3 and OV-rich WO3- x nanosheets are first prepared by simple calcination of the WO3 ·H2 O nanosheets under an air and N2 atmosphere, respectively. Pt, Cu, Fe, Co, and Ni metal SAs are then deposited on WO3- x nanosheets to obtain metal SA-decorated WO3- x nanocomposites (M-WO3- x ). Importantly, the Cu-WO3- x sonosensitizer exhibits a much higher activity for ultrasound (US)-induced production of reactive oxygen species than that of the WO3- x and Cu SA-decorated WO3 , which is also higher than other M-WO3- x nanosheets. Both the experimental and theoretical results suggest that the excellent SDT performance of the Cu-WO3- x nanosheets should be attributed to the synergistic effect between Cu SAs and WO3- x OVs. Therefore, after polyethylene glycol modification, the Cu-WO3- x can quickly kill cancer cells in vitro and effectively eradicate tumors in vivo under US irradiation. Transcriptome sequencing analysis and further molecular validation suggest that the Cu-WO3- x -mediated SDT-activated apoptosis and TNF signaling pathways are potential drivers of tumor apoptosis induction.

Adipocyte-Specific Hnrnpa1 Knockout Aggravates Obesity-Induced Metabolic Dysfunction via Upregulation of CCL2.

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is involved in lipid and glucose metabolism via mRNA processing. However, whether and how HNRNPA1 alters adipocyte function in obesity remain obscure. Here, we found that the obese state downregulated HNRNPA1 expression in white adipose tissue (WAT). The depletion of adipocyte HNRNPA1 promoted markedly increased macrophage infiltration and expression of proinflammatory and fibrosis genes in WAT of obese mice, eventually leading to exacerbated insulin sensitivity, glucose tolerance, and hepatic steatosis. Mechanistically, HNRNPA1 interacted with Ccl2 and regulated its mRNA stability. Intraperitoneal injection of CCL2-CCR2 signaling antagonist improved adipose tissue inflammation and systemic glucose homeostasis. Furthermore, HNRNPA1 expression in human WAT was negatively correlated with BMI, fat percentage, and subcutaneous fat area. Among individuals with 1-year metabolic surgery follow-up, HNRNPA1 expression was positively related to percentage of total weight loss. These findings identify adipocyte HNRNPA1 as a link between adipose tissue inflammation and systemic metabolic homeostasis, which might be a promising therapeutic target for obesity-related disorders.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

Elevated CD4+ T Cell Senescence Associates with Impaired Immune Responsiveness in Severe COVID-19.

Aging is a critical risk factor for unfavorable clinical outcomes among COVID-19 patients and may impact vaccine efficacy. However, whether the senescence of T cells is associated with severe COVID-19 outcome in elderly individuals is unclear. Using flow cytometry, we analyzed the frequency of senescent T cells (Tsens) in peripheral blood from 100 hospitalized elderly COVID-19 patients and compared differences between those with mild/moderate and severe/critical illness. We also assessed correlations between the percentage of Tsens and the quantity and quality of spike-specific antibodies by ELISA, neutralizing antibody test kit, and ELISPOT assay respectively, the cytokine production profile of COVID-19 reactive T cells, and plasma soluble factors by cytometric bead array (CBA). Our study found a significantly elevated level of CD4+ Tsens in patients with severe/critical disease compared to those with mild/moderate illness. Patients with a higher level of CD4+ Tsens (>19.78%) showed a decreased survival rate compared to those with a lower level (≤19.78%). This is more pronounced among patients with breakthrough infections. The percentage of CD4+ Tsens was negatively correlated with spike-specific antibody titers, neutralization ability, and COVID-19 reactive IL-2+CD4+ T cells. In addition, spike-specific antibody levels were positively correlated with IL-2 producing T cells and plasma IL-2 amount. Mechanistically, with defective CD40L, T cells from patients with CD4+ Tsens >19.78% were unable to support B cell proliferation and differentiation. Our data demonstrate that the percentage of CD4+ Tsens in peripheral blood may serve as a reliable biomarker for the prognosis of severe COVID-19 patients, especially in breakthrough infections. Therefore, restoring the immune response of CD4+ Tsens may be key to preventing severe illness and improving vaccine efficacy in older adults.

An Intelligent and Soluble Microneedle Composed of Bi/BiVO4 Schottky Heterojunction for Tumor Ct Imaging and Starvation/Gas Therapy-Promoted Synergistic Cancer Treatment.

Phototherapy and sonodynamic therapy (SDT) are widely used for the synergistic treatment of tumors and have received considerable attention. However, an inappropriate tumor microenvironment, including pH, H2O2, oxygen, and glutathione levels, can reduce the therapeutic effects of synergistic phototherapy and SDT. Here, a novel Bi-based soluble microneedle (MN) is designed for the CT imaging of breast tumors and starvation therapy/gas therapy-enhanced phototherapy/SDT. The optimized Bi/BiVO4 Schottky heterojunction serves as the tip of the MN, which not only has excellent photothermal conversion ability and CT contrast properties, but its heterojunction can also avoid the rapid combination of electrons and hole pairs, thereby enhancing the photodynamic/sonodynamic effects. A degradable MN with excellent mechanical properties is fabricated by optimizing the ratios of poly(vinyl alcohol), poly(vinyl pyrrolidone), and sodium hyaluronate. Glucose oxidase (GOx) and diallyl trisulfide are loaded into the MN to achieve tumor starvation and gas therapy, respectively; And the controlled release of GOx and H2S can be achieved under ultrasound or near-infrared laser irradiation. The in vitro and in vivo results demonstrate that this multifunctional MN can achieve high therapeutic efficacy through starvation therapy/gas therapy-enhanced phototherapy/SDT. The designed multifunctional MN provides a prospective approach for synergistic phototherapy and SDT.

Mir-338-3p targeting THBS1 attenuates glioma progression by inhibiting the PI3K/Akt pathway.

BACKGROUND: Glioma is a brain tumor with high morbidity and mortality rates. Understanding its molecular pathogenesis can provide targets and therapeutic strategies for glioma treatment. miR-338-3p represses tumor growth in several cancers, including glioma. Thus, this study aimed to identify the regulatory effects of miR-338-3p/phosphoinositide 3-kinase (PI3K)/Akt/thrombospondins 1 (THBS1) on glioma progression. MATERIALS AND METHODS: Quantitative reverse transcription polymerase chain reaction and western blotting were performed to evaluate the levels of miR-338-3p, THBS1, and PI3K/Akt phosphorylation-related proteins. TargetScan software predicted that miR-338-3p targeted THBS1. This was confirmed by performing the dual-luciferase assay. Wound-healing and cell-counting-kit-8 experiments were performed to analyze how THBS1 and miR-338-3p affect the ability of glioma cells to migrate and proliferate. The effect of miR-338-3p on tumorigenicity in mice was also analyzed. RESULTS: miR-338-3p downregulation was observed in gliomas, whereas THBS1 showed the opposite trend. By suppressing the PI3K/Akt signaling pathway activation, miR-338-3p overregulated the ability of glioma cells to migrate and proliferate in vitro. Additionally, miR-338-3p inhibited the development of glioma tumors in vivo. Moreover, miR-338-3p directly targeted THBS1. THBS1 overexpression promoted glioma cell migration and proliferation by increasing PI3K/Akt phosphorylation. Nonetheless, miR-338-3p overregulation alleviated the effects of THBS1 overexpression. CONCLUSION: The miR-338-3p/PI3K/Akt/THBS1 regulatory axis can modulate the progression of glioma cell proliferation and migration; thus, it can be considered a therapeutic biomarker.

Preparation and performance of biocompatible gadolinium polymer as liver-targeting magnetic resonance imaging contrast agent.

A biocompatible macromolecule-conjugated gadolinium chelate complex (PAV2-EDA-DOTA-Gd) as a new liver-specific contrast agent for magnetic resonance imaging (MRI) was synthesized and evaluated. An aspartic acid-valine copolymer was used as a carrier and ethylenediamine as a chemical linker, and the aspartic acid-valine copolymer was covalently linked to the small molecule MRI contrast agent Gd-DOTA (Dotarem) to synthesize a large molecule contrast agent. In vitro MR relaxation showed that the T1-relaxivity of PAV2-EDA-DOTA-Gd (13.7 mmol-1 L s-1) was much higher than that of the small-molecule Gd-DOTA (4.9 mmol-1 L s-1). In vivo imaging of rats showed that the enhancement effect of PAV2-EDA-DOTA-Gd (55.37 ± 2.80%) on liver imaging was 2.6 times that of Gd-DOTA (21.12 ± 3.86%), and it produced a longer imaging window time (40-70 min for PAV2-EDA-DOTA-Gd and 10-30 min for Gd-DOTA). Preliminary safety experiments, such as cell experiments and tissue sectioning, showed that PAV2-EDA-DOTA-Gd had low toxicity and satisfactory biocompatibility. The results of this study indicated that PAV2-EDA-DOTA-Gd had high potential as a liver-specific MRI contrast agent.