A review of the ecotoxicological status of microplastic pollution in African freshwater systems.

Microplastics (MPs) have found extensive application globally due to their low cost, flexibility and light weight. Microplastic pollution is a growing environmental concern that poses significant threats to aquatic ecosystems worldwide, including African freshwater systems. Nevertheless, although Africa houses some of the deepest and largest freshwater rivers and lakes in the world such as Lake Tanganyika and Victoria, River Congo and the Nile, there is limited information available regarding the presence of MPs in these inland waters. Selected published data on MPs in African freshwater systems, including sediments, biota, rivers, and lakes, were incorporated in this review. The study discovered that the sampling technique employed has a major impact on the morphological characteristics and abundance of MPs in African freshwater systems. Fibers and fragments were the most common shapes; black, white, and transparent were the most prevalent colors; and polyethene terephthalate, polystyrene, and polypropylene were the frequently dominant polymers. As the distance between the sampling sites increased geographically, the polymer similarities declined. MPs have been found to translocate into body cells and tissues where they are capable of causing genetic mutations, cytotoxicity, oxidative stress and neurotoxicity. In Africa, MPs are poorly managed and monitored, and there has been insufficient research done on the possibility that they could be present in drinking water. Considering the fact that humans in the continent are exposed to freshwater and aquatic organisms, the risk assessment routes are currently unvalidated, therefore it was recommended that African nations should strengthen their capacity for plastic management and environmental monitoring. This review provides up to date information on the occurrence, prevalence, ecotoxicity and management of MPs across African freshwater systems.

A multi-institutional comparison of retrospective deformable dose accumulation for online adaptive magnetic resonance-guided radiotherapy.

Background and Purpose: Application of different deformable dose accumulation (DDA) solutions makes institutional comparisons after online-adaptive magnetic resonance-guided radiotherapy (OA-MRgRT) challenging. The aim of this multi-institutional study was to analyze accuracy and agreement of DDA-implementations in OA-MRgRT. Material and Methods: One gold standard (GS) case deformed with a biomechanical-model and five clinical cases consisting of prostate (2x), cervix, liver, and lymph node cancer, treated with OA-MRgRT, were analyzed. Six centers conducted DDA using institutional implementations. Deformable image registration (DIR) and DDA results were compared using the contour metrics Dice Similarity Coefficient (DSC), surface-DSC, Hausdorff-distance (HD95%), and accumulated dose-volume histograms (DVHs) analyzed via intraclass correlation coefficient (ICC) and clinical dosimetric criteria (CDC). Results: For the GS, median DDA errors ranged from 0.0 to 2.8 Gy across contours and implementations. DIR of clinical cases resulted in DSC > 0.8 for up to 81.3% of contours and a variability of surface-DSC values depending on the implementation. Maximum HD95%=73.3 mm was found for duodenum in the liver case. Although DVH ICC > 0.90 was found after DDA for all but two contours, relevant absolute CDC differences were observed in clinical cases: Prostate I/II showed maximum differences in bladder V28Gy (10.2/7.6%), while for cervix, liver, and lymph node the highest differences were found for rectum D2cm3 (2.8 Gy), duodenum Dmax (7.1 Gy), and rectum D0.5cm3 (4.6 Gy). Conclusion: Overall, high agreement was found between the different DIR and DDA implementations. Case- and algorithm-dependent differences were observed, leading to potentially clinically relevant results. Larger studies are needed to define future DDA-guidelines.

Trichostatin A Promotes Cytotoxicity of Cisplatin, as Evidenced by Enhanced Apoptosis/Cell Death Markers.

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the cytotoxicity of the genotoxic anticancer drug cisplatin, yet the underlying mechanism remains poorly understood. Herein, we revealed that TSA at a low concentration (1 µM) promoted the cisplatin-induced activation of caspase-3/6, which, in turn, increased the level of cleaved PARP1 and degraded lamin A&C, leading to more cisplatin-induced apoptosis and G2/M phase arrest of A549 cancer cells. Both ICP-MS and ToF-SIMS measurements demonstrated a significant increase in DNA-bound platinum in A549 cells in the presence of TSA, which was attributable to TSA-induced increase in the accessibility of genomic DNA to cisplatin attacking. The global quantitative proteomics results further showed that in the presence of TSA, cisplatin activated INF signaling to upregulate STAT1 and SAMHD1 to increase cisplatin sensitivity and downregulated ICAM1 and CD44 to reduce cell migration, synergistically promoting cisplatin cytotoxicity. Furthermore, in the presence of TSA, cisplatin downregulated TFAM and SLC3A2 to enhance cisplatin-induced ferroptosis, also contributing to the promotion of cisplatin cytotoxicity. Importantly, our posttranslational modification data indicated that acetylation at H4K8 played a dominant role in promoting cisplatin cytotoxicity. These findings provide novel insights into better understanding the principle of combining chemotherapy of genotoxic drugs and HDAC inhibitors for the treatment of cancers.

Dihydroartemisinin induces ferroptosis in T cell acute lymphoblastic leukemia cells by downregulating SLC7A11 and activating the ATF4­CHOP signaling pathway.

The present study aimed to investigate the anti-leukemic effects of dihydroartemisinin (DHA) on T-cell acute lymphoblastic leukemia (T-ALL) cell lines, Jurkat and Molt-4, and the underlying mechanisms. Cell Counting Kit-8 was performed to measure cell viability. Cell apoptosis and cell cycle distribution were assessed by flow cytometry. The expression levels of ATF4 and CHOP mRNA were assessed by reverse transcription-quantitative PCR, while the protein abundance of SLC7A11, GPX4, ATF4 and CHOP was determined by western blotting. Moreover, malondialdehyde, glutathione (GSH) and reactive oxygen species (ROS) assays were used to detect the levels of ferroptosis. The results showed that DHA suppressed T-ALL cell viability in vitro, and induced cell cycle arrest at S or G2/M phase. DHA also induced ROS burst, activated endoplasmic reticulum (ER) stress, disrupted the system Xc--GSH-GSH peroxidase 4 antioxidant system, and increased lipid peroxide accumulation, resulting in cell death. By contrast, the pharmacological inhibition of ferroptosis alleviated DHA-induced cell death, confirming that DHA induces T-ALL cell death via ferroptosis. Mechanistically, the effect of DHA on ferroptosis was partly mediated by downregulating SLC7A11 and upregulating the ATF4-CHOP signaling pathway, which is associated with ER stress. These results indicated that DHA may induce ferroptosis in T-ALL cell lines and could represent a promising therapeutic agent for treating T-ALL.

Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

PURPOSE: Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. METHODS: The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. RESULTS: Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). CONCLUSION: Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

Multi-modal segmentation with missing image data for automatic delineation of gross tumor volumes in head and neck cancers.

BACKGROUND: Head and neck (HN) gross tumor volume (GTV) auto-segmentation is challenging due to the morphological complexity and low image contrast of targets. Multi-modality images, including computed tomography (CT) and positron emission tomography (PET), are used in the routine clinic to assist radiation oncologists for accurate GTV delineation. However, the availability of PET imaging may not always be guaranteed. PURPOSE: To develop a deep learning segmentation framework for automated GTV delineation of HN cancers using a combination of PET/CT images, while addressing the challenge of missing PET data. METHODS: Two datasets were included for this study: Dataset I: 524 (training) and 359 (testing) oropharyngeal cancer patients from different institutions with their PET/CT pairs provided by the HECKTOR Challenge; Dataset II: 90 HN patients(testing) from a local institution with their planning CT, PET/CT pairs. To handle potentially missing PET images, a model training strategy named the "Blank Channel" method was implemented. To simulate the absence of a PET image, a blank array with the same dimensions as the CT image was generated to meet the dual-channel input requirement of the deep learning model. During the model training process, the model was randomly presented with either a real PET/CT pair or a blank/CT pair. This allowed the model to learn the relationship between the CT image and the corresponding GTV delineation based on available modalities. As a result, our model had the ability to handle flexible inputs during prediction, making it suitable for cases where PET images are missing. To evaluate the performance of our proposed model, we trained it using training patients from Dataset I and tested it with Dataset II. We compared our model (Model 1) with two other models which were trained for specific modality segmentations: Model 2 trained with only CT images, and Model 3 trained with real PET/CT pairs. The performance of the models was evaluated using quantitative metrics, including Dice similarity coefficient (DSC), mean surface distance (MSD), and 95% Hausdorff Distance (HD95). In addition, we evaluated our Model 1 and Model 3 using the 359 test cases in Dataset I. RESULTS: Our proposed model(Model 1) achieved promising results for GTV auto-segmentation using PET/CT images, with the flexibility of missing PET images. Specifically, when assessed with only CT images in Dataset II, Model 1 achieved DSC of 0.56 ± 0.16, MSD of 3.4 ± 2.1 mm, and HD95 of 13.9 ± 7.6 mm. When the PET images were included, the performance of our model was improved to DSC of 0.62 ± 0.14, MSD of 2.8 ± 1.7 mm, and HD95 of 10.5 ± 6.5 mm. These results are comparable to those achieved by Model 2 and Model 3, illustrating Model 1's effectiveness in utilizing flexible input modalities. Further analysis using the test dataset from Dataset I showed that Model 1 achieved an average DSC of 0.77, surpassing the overall average DSC of 0.72 among all participants in the HECKTOR Challenge. CONCLUSIONS: We successfully refined a multi-modal segmentation tool for accurate GTV delineation for HN cancer. Our method addressed the issue of missing PET images by allowing flexible data input, thereby providing a practical solution for clinical settings where access to PET imaging may be limited.

Lymphocyte counts predict optimal timing of chemotherapy reinitiation after antivirus treatment for herpes zoster in children with leukemia.

Herpes zoster (HZ) is rare in healthy children, but more prevalent in those with leukemia. Optimal timing of chemotherapy reinitiation after HZ treatment is challenging because chemotherapy suppresses immunity and increases risk of HZ relapse. We aimed to optimize the timing of chemotherapy reinitiation after HZ therapy in children with leukemia. The study included 31 children with acute leukemia and HZ infection. General information, clinical symptoms, laboratory test results, duration of HZ treatment, and prognosis were compared with those of children with leukemia alone. Correlation analysis was performed for 20 children who restarted chemotherapy after HZ treatment. Of 31 children with leukemia and HZ, 67.74% had lesions at multiple sites. The median time from chemotherapy initiation to HZ onset was 14.1 (1.5-29.5) months. Among 27 children included in the follow-up, there was one case of HZ relapse. After excluding children who did not continue chemotherapy after HZ treatment, the median interval between completion of HZ therapy and chemotherapy reinitiation in the remaining 20 children was 8.00 (- 3 to 27) days. Lymphocyte counts (LY#) on restarting chemotherapy correlated inversely with HZ lesion healing time (p < 0.05). LY# at the time of HZ onset were lower than those pre- and post-onset, and lower than those in the control group (p < 0.05). In conclusion, children with leukemia have a good HZ prognosis, but an increased risk of HZ recurrence. LY# at the time of chemotherapy reinitiation may be a useful indicator for selecting the optimal interval between antiviral therapy completion and chemotherapy reinitiation.

De novo design of SARS-CoV-2 main protease inhibitors with characteristic binding modes.

The coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly all over the world. The main protease (Mpro) is significant to the replication and transcription of viruses, making it an attractive drug target against coronaviruses. Here, we introduce a series of novel inhibitors which are designed de novo through structure-based drug design approach that have great potential to inhibit SARS-CoV-2 Mproin vitro. High-resolution structures show that these inhibitors form covalent bonds with the catalytic cysteine through the novel dibromomethyl ketone (DBMK) as a reactive warhead. At the same time, the designed phenyl group beside the DBMK warhead inserts into the cleft between H41 and C145 through π-π stacking interaction, splitting the catalytic dyad and disrupting proton transfer. This unique binding model provides novel clues for the cysteine protease inhibitor development of SARS-CoV-2 as well as other pathogens.

Effect of Topical Application of an NSAID Lateral to the Incision on Postoperative Pain Following Unicompartmental Knee Arthroplasty: A Double-Blind Randomized Controlled Trial.

OBJECTIVE: How to minimize postoperative pain following knee replacement surgery has been a great challenge. This study was performed to evaluate the effect of applying a topical nonsteroidal anti-inflammatory drug (NSAID) lateral to the incision for postoperative pain following unicompartmental knee arthroplasty (UKA). METHODS: The randomized controlled trial enrolled 100 patients from August 2023 to January 2024. One hundred patients who underwent UKA were randomized into two groups. The intervention group received a topical NSAID lateral to the incision postoperatively, and the control group received a placebo lateral to the incision postoperatively. The primary outcome measures were the amount of opioid consumption and the visual analogue scale (VAS) score (12, 24, 36, 48, and 72 h after operation) for pain. The secondary outcome measures were the American Knee Society Score (AKSS, preoperation and 1-month follow-up after operation), the time of first analgesic demand, side effects of opioids, operation time, postoperative stay, surgery-related complications, and postoperative incision healing grade. Independent sample t test and paired sample t test were used to compare continuous data. Chi-square test and Fisher's precision probability tests were used to analyze the categorical data. RESULTS: Ninety-eight patients (intervention group, 48 patients; control group, 50 patients) were analyzed. Opioid consumption was significantly lower in the intervention group than in the control group during the first 12 h, 12 to 24 h, and 24 to 48 h postoperatively (p < 0.05). The VAS score for pain within 72 h postoperatively was significantly lower in the intervention group than in the control group (p < 0.05). There was no significant difference in the AKSS, operation time, postoperative stay, complications, or postoperative incision healing grade between the two groups. The time of first analgesic demand for patient-controlled analgesia was significantly later in the intervention group than in the control group (p < 0.05). There were fewer side effects of opioids in the intervention group (8.3%) than in the control group (18.0%). CONCLUSION: Postoperative application of topical NSAIDs lateral to the incision is an effective and safe method for pain management after UKA, helping to decrease the pain score and reduce opioid consumption postoperatively with no increase in side effects.

Black phosphorus, an advanced versatile nanoparticles of antitumor, antibacterial and bone regeneration for OS therapy.

Osteosarcoma (OS) is the most common primary malignant bone tumor. In the clinic, usual strategies for OS treatment include surgery, chemotherapy, and radiation. However, all of these therapies have complications that cannot be ignored. Therefore, the search for better OS treatments is urgent. Black phosphorus (BP), a rising star of 2D inorganic nanoparticles, has shown excellent results in OS therapy due to its outstanding photothermal, photodynamic, biodegradable and biocompatible properties. This review aims to present current advances in the use of BP nanoparticles in OS therapy, including the synthesis of BP nanoparticles, properties of BP nanoparticles, types of BP nanoparticles, and modification strategies for BP nanoparticles. In addition, we have discussed comprehensively the application of BP in OS therapy, including single, dual, and multimodal synergistic OS therapies, as well as studies about bone regeneration and antibacterial properties. Finally, we have summarized the conclusions, limitations and perspectives of BP nanoparticles for OS therapy.

RedCDR: Dual Relation Distillation for Cancer Drug Response Prediction.

Based on multi-omics data and drug information, predicting the response of cancer cell lines to drugs is a crucial area of research in modern oncology, as it can promote the development of personalized treatments. Despite the promising performance achieved by existing models, most of them overlook the variations among different omics and lack effective integration of multi-omics data. Moreover, the explicit modeling of cell line/drug attribute and cell line-drug association has not been thoroughly investigated in existing approaches. To address these issues, we propose RedCDR, a dual relation distillation model for cancer drug response (CDR) prediction. Specifically, a parallel dual-branch architecture is designed to enable both the independent learning and interactive fusion feasible for cell line/drug attribute and cell line-drug association information. To facilitate the adaptive interacting integration of multi-omics data, the proposed multi-omics encoder introduces the multiple similarity relations between cell lines and takes the importance of different omics data into account. To accomplish knowledge transfer from the two independent attribute and association branches to their fusion, a dual relation distillation mechanism consisting of representation distillation and prediction distillation is presented. Experiments conducted on the GDSC and CCLE datasets show that RedCDR outperforms previous state-of-the-art approaches in CDR prediction. The source code is available at https://github.com/mhxu1998/RedCDR.

LncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas.

Arteriovenous fistulas (AVFs) are the most common vascular access points for hemodialysis (HD), but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia (NIH). Our previous studies have revealed a highly conserved LncRNA-LncDACH1 as an important regulator of cardiomyocyte and fibroblast proliferation. Herein, we find that LncDACH1 regulates NIH in AVF in male mice with conditional knockout of smooth muscle cell-specific LncDACH1 and in male mice model of AVF with LncDACH1 overexpression by adeno-associated virus. Mechanistically, silence of LncDACH1 activates p-AKT through promoting the expression of heat shock protein 90 (HSP90) and serine/arginine-rich splicing factor protein kinase 1 (SRPK1). Moreover, LncDACH1 is transcriptionally activated by transcription factor KLF9 that binds directly to the promoter region of the LncDACH1 gene. In this work, during AVF NIH, LncDACH1 is downregulated by KLF9 and promotes NIH through the HSP90/ SRPK1/ AKT signaling axis.

Cardioprotective potentials of myricetin on doxorubicin-induced cardiotoxicity based on biochemical and transcriptomic analysis.

Doxorubicin (DOX) is a commonly used anthracycline in cancer chemotherapy. The clinical application of DOX is constrained by its cardiotoxicity. Myricetin (MYR) is a natural flavonoid widely present in many plants with antioxidant and anti-inflammatory properties. However, MYR's beneficial effects and mechanisms in alleviating DOX-induced cardiotoxicity (DIC) remain unknown. C57BL/6 mice were injected with 15 mg/kg of DOX to establish the DIC, and MYR solutions were administrated by gavage to investigate its cardioprotective potentials. Histopathological analysis, physiological indicators assessment, transcriptomics analysis, and RT-qPCR were used to elucidate the potential mechanism of MYR in DIC treatment. MYR reduced cardiac injury produced by DOX, decreased levels of cTnI, AST, LDH, and BNP, and improved myocardial injury and fibrosis. MYR effectively prevented DOX-induced oxidative stress, such as lowered MDA levels and elevated SOD, CAT, and GSH activities. MYR effectively suppressed NLRP3 and ASC gene expression levels to inhibit pyroptosis while regulating Caspase1 and Bax levels to reduce cardiac cell apoptosis. According to the transcriptomic analysis, glucose and fatty acid metabolism were associated with differential gene expression. KEGG pathway analysis revealed differential gene enrichment in PPAR and AMPK pathways, among others. Following validation, MYR was found to alleviate DIC by regulating glycolipid metabolism and AMPK pathway-related genes. Our findings demonstrated that MYR could mitigate DIC by regulating the processes of oxidative stress, apoptosis, and pyroptosis. MYR is critical in improving DOX-induced myocardial energy metabolism abnormalities mediated by the AMPK signaling pathway. In conclusion, MYR holds promise as a therapeutic strategy for DIC.

Carboxymethylated Rhizoma alismatis polysaccharides reduces the risk of calcium oxalate stone formation by reducing cellular inflammation and oxidative stress.

This study aims to elucidate the mechanism and potential of Rhizoma alismatis polysaccharides (RAPs) in preventing oxidative damage to human renal proximal tubule epithelial cells. The experimental approach involved incubating HK-2 cells with 100 nm calcium oxalate monohydrate for 24 h to establish a cellular injury model. Protection was provided by RAPs with varying carboxyl group contents: 3.57%, 7.79%, 10.84%, and 15.33%. The safeguarding effect of RAPs was evaluated by analyzing relevant cellular biochemical indicators. Findings demonstrate that RAPs exhibit notable antioxidative properties. They effectively diminish the release of reactive oxygen species, lactate dehydrogenase, and malondialdehyde, a lipid oxidation byproduct. Moreover, RAPs enhance superoxide dismutase activity and mitochondrial membrane potential while attenuating the permeability of the mitochondrial permeability transition pore. Additionally, RAPs significantly reduce levels of inflammatory factors, including NLRP3, TNF-α, IL-6, and NO. This reduction corresponds to the inhibition of overproduced pro-inflammatory mediator nitric oxide and the caspase 3 enzyme, leading to a reduction in cellular apoptosis. RAPs also display the ability to suppress the expression of the HK-2 cell surface adhesion molecule CD44. The observed results collectively underscore the substantial anti-inflammatory and anti-apoptotic potential of all four RAPs. Moreover, their capacity to modulate the expression of cell surface adhesion molecules highlights their potential in inhibiting the formation of kidney stones. Notably, RAP3, boasting the highest carboxyl group content, emerges as the most potent agent in this regard.

A Platinum-Aluminum Bimetallic Salen Complex for Pro-senescence Cancer Therapy.

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.

Carboxymethylated Desmodium styracifolium polysaccharide reduces the risk of calcium oxalate kidney stone formation by inhibiting crystal adhesion and promoting crystal endocytosis.

The inhibition of cell surface crystal adhesion and an appropriate increase in crystal endocytosis contribute to the inhibition of kidney stone formation. In this study, we investigated the effects of different degrees of carboxymethylation on these processes. An injury model was established by treating human renal proximal tubular epithelial (HK-2) cells with 98.3 ± 8.1 nm calcium oxalate dihydrate (nanoCOD) crystals. The HK-2 cells were protected with carboxy (-COOH) Desmodium styracifolium polysaccharides at 1.17% (DSP0), 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3). Changes in biochemical indexes and effects on nanoCOD adhesion and endocytosis were detected. The protection of HK-2 cells from nanoCOD-induced oxidative damage by carboxymethylated Desmodium styracifolium polysaccharides (CDSPs) is closely related to the protection of subcellular organelles, such as mitochondria. CDSPs can reduce crystal adhesion on the cell surface and maintain appropriate crystal endocytosis, thereby reducing the risk of kidney stone formation. CDSP2 with moderate -COOH content showed the strongest protective activity among the CDSPs.

SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.

BACKGROUND: SIRPB1 expression is upregulated in various tumor types, including gliomas, and is known to contribute to tumor progression; nevertheless, its function in the immune milieu of gliomas is still mainly unknown. METHODS: This study, we analyzed 1152 normal samples from the GTEx database and 670 glioma samples from the TCGA database to investigate the relationship between the expression of SIRPB1 and clinicopathological features. Moreover, SIRPB1 gene knockout THP-1 cell lines were constructed using CRISPR/Cas9 and were induced into a co-culture of macrophages and glioma cells in vitro to learn more about the role of SIRPB1 in the glioma immune milieu. Lastly, we established a prognostic model to predict the effect of SIRPB1 on prognosis. RESULTS: Significantly higher levels of SIRPB1 expression were found in gliomas, which had an adverse effect on the immune milieu and correlated poorly with patient survival. SIRPB1 activation with certain antibodies results in SYK phosphorylation and the subsequent activation of calcium, MAPK, and NF-κB signaling pathways. This phenomenon is primarily observed in myeloid-derived cells as opposed to glioma cells. In vitro co-culture demonstrated that macrophages with SIRPB1 knockout showed decreased IL1RA, CCL2, and IL-8, which were recovered upon ectopic expression of SIRPB1 but reduced again following treatment with SYK inhibitor GS9973. Critically, a lower overall survival rate was linked to increased SIRPB1 expression. Making use of SIRPB1 expression along with additional clinicopathological variables, we established a nomogram that showed a high degree of prediction accuracy. CONCLUSIONS: Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas.

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1.

Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

CHRNA9 as a New Prognostic Marker and Potential Therapeutic Target in Glioma.

Background: The nicotinic acetylcholine receptor (nAChR) subunit alpha-9 (CHRNA9) is a unique cholinergic receptor, which is involved in tumor proliferation, apoptosis, metastasis and chemotherapy resistance. However, the correlation between the expression level of CHRNA9 in glioma and the clinical features and prognosis of glioma patients has not been clarified. The aim of this study was to verify the expression level of CHRNA9 in glioma and its effect on prognosis by bioinformatics methods. Methods: The RNA-seq data of glioma and normal samples were obtained from the TCGA and GTEx databases. Bioinformatics methods were utilized to analyze the differential expression of CHRNA9 between tumor samples and normal samples. The potential association between CHRNA9 and the clinicopathological features of glioma patients was also investigated. The Kaplan-Meier method and Cox regression were utilized to analyze the relationship between CHRNA9 expression level and survival time and prognostic value of glioma patients. Enrichment analysis was applied to predict gene function and signaling pathways associated with CHRNA9. Experimental verification was performed using tumor tissues and paracancerous tissues from glioma patients. Results: The results of bioinformatics analysis showed that the expression of CHRNA9 was increased in glioma tissues, correlating with poor prognosis and reduced patient survival time. Enrichment analysis suggested that CHRNA9 may interact with the JAK/STAT pathway. CHRNA9 was also found to be abnormally expressed in various other tumors and associated with the expression levels of numerous immune checkpoints in glioma. The findings from the analysis of clinical samples revealed that the expression levels of both mRNA and protein of CHRNA9 in glioma tissues were higher than those in paracancerous tissues. Similarly, the mRNA expression levels of STAT3, IL-6, and TNF-α, which are crucial factors in the STAT3 pathway, were elevated in glioma tissues compared to paracancerous tissues. Conclusion: CHRNA9 is a potential prognostic marker and immunotherapy target for glioma, with its mechanism of action potentially linked to the STAT3 pathway.

Combined simultaneous transsphenoidal and transcranial regimen improves surgical outcomes in complex giant pituitary adenomas: A longitudinal retrospective cohort study.

BACKGROUND: Surgical treatment of complex giant pituitary adenomas (GPAs) presents significant challenges. The efficacy and safety of combining transsphenoidal and transcranial approaches for these tumors remain controversial. In this largest cohort of patients with complex GPAs, we compared the surgical outcomes between those undergoing a combined regimen and a non-combined regimen. We also examined the differences in risks of complications, costs, and logistics between the two groups, which might offer valuable information for the appropriate management of these patients. MATERIALS AND METHODS: This was a multicenter retrospective cohort study conducted at 13 neurosurgical centers. Consecutive patients who received a combined or non-combined regimen for complex GPAs were enrolled. The primary outcome was gross total resection, while secondary outcomes included complications, surgical duration, and relapse. A propensity score-based weighting method was used to account for differences between the groups. RESULTS: Out of 647 patients (298 [46.1%] women, mean age: 48.5 ± 14.0 years) with complex GPAs, 91 were in the combined group and 556 were in the non-combined group. Compared with the non-combined regimen, the combined regimen was associated with a higher probability of gross total resection (50.5% vs. 40.6%, odds ratio [OR]: 2.18, 95% confidence interval [CI]: 1.30-3.63, P = 0.003). The proportion of patients with life-threatening complications was lower in the combined group than in the non-combined group (4.4% vs. 11.2%, OR: 0.25, 95% CI: 0.08-0.78, P = 0.017). No marked differences were found between the groups in terms of other surgical or endocrine-related complications. However, the combined regimen exhibited a longer average surgery duration of 1.3 h (P < 0.001) and higher surgical costs of 22,000 CNY (approximate 3,000 USD, P = 0.022) compared with the non-combined approach. CONCLUSIONS: The combined regimen offered increased rates of total resection and decreased incidence of life-threatening complications, which might be recommended as the first-line choice for these patients.