Potential clinical application of microRNAs in bladder cancer.

Bladder cancer (BC) is the tenth most prevalent malignancy globally, presenting significant clinical and societal challenges because of its high incidence, rapid progression, and frequent recurrence. Presently, cystoscopy and urine cytology serve as the established diagnostic methods for BC. However, their efficacy is limited by invasive nature and low sensitivity. Therefore, the development of highly specific biomarkers and effective non-invasive detection strategies is imperative for achieving a precise and timely diagnosis of BC, as well as for facilitating an optimal tumor treatment and an improved prognosis. microRNAs (miRNAs), short noncoding RNA molecules spanning around 20-25 nucleotides, are implicated in the regulation of diverse carcinogenic pathways. Substantially altered miRNAs form robust functional regulatory networks that exert a notable influence on the tumorigenesis and progression of BC. Investigations into aberrant miRNAs derived from blood, urine, or extracellular vesicles indicate their potential roles as diagnostic biomarkers and prognostic indicators in BC, enabling miRNAs to monitor the progression and predict the recurrence of the disease. Simultaneously, the investigation centered on miRNA as a potential therapeutic agent presents a novel approach for the treatment of BC. This review provides a comprehensive analysis of the biological roles of miRNAs in tumorigenesis and progression, and systematically summarizes the potential as diagnosis and prognosis biomarkers as well as therapeutic targets for BC. Additionally, we evaluate the progress made in laboratory techniques within this field and discuss the prospects.

Plasma Thioredoxin Reductase as a Potential Diagnostic Biomarker for Breast Cancer.

BACKGROUND: Early diagnosis of breast cancer is critical to the treatment and prognosis of breast cancer patients. Our aim is to explore more practical and effective diagnostic methods to facilitate early treatment and improve prognosis for breast cancer patients. MATERIALS AND METHODS: The Mann-Whitney U test, receiver operating characteristic curve, Youden index, Chi-square test, and Fisher's exact test were used to determine whether plasma thioredoxin reductase (TrxR) could be used for the clinical diagnosis of breast cancer. The Wilcoxon signed-rank test was used to validate the prognostic potential of plasma TrxR activity assessment. RESULTS: A total of 761 patients were included, including 537 cases of breast cancer and 224 cases of benign breast diseases. Plasma TrxR activity in the breast cancer group [8.0 (6.0, 9.45) U/mL] was significantly higher than that in the benign group [3.05 (1.20, 6.275) U/mL]. The diagnostic efficiency of TrxR for breast cancer was higher than that of other conventional breast cancer biomarkers, with an area under the curve of 0.821 (95% CI = 0.791-0.852). In addition, TrxR can be used in combination with conventional tumor markers to further improve the diagnostic efficiency. The optimal TrxR threshold for identifying benign and malignant diseases is 7.45 U/mL. We detected plasma TrxR activity and serum tumor markers before and after antitumor therapies in 333 breast cancer patients and found that their trends were basically the same, with a significant decrease in plasma TrxR activity after treatment. CONCLUSION: Plasma TrxR activity can be used as a suitable biomarker for breast cancer diagnosis and efficacy assessment.

Amplification-Free Analysis of Bladder Cancer MicroRNAs on Wrinkled Silica Nanoparticles with DNA-Functionalized Quantum Dots.

Bladder cancer (BC) occurrence and progression are accompanied by alterations in microRNAs (miRNAs) expression levels. Simultaneous detection of multiple miRNAs contributes to the accuracy and reliability of the BC diagnosis. In this work, wrinkled silica nanoparticles (WSNs) were applied as the microreactor for multiplex miRNAs analysis without enzymes or nucleic acid amplification. Conjugated on the surface of WSNs, the S9.6 antibody was adopted as the universal module for binding DNA/miRNA duplexes, regardless of their sequence. Furthermore, single-stranded DNA (ssDNA) was labeled with quantum dots (QDs) for identifying a given miRNA to form QDs-ssDNA/miRNA, which enabled the specific capture of the corresponding QDs on the wrinkled surface of WSNs. Based on the detection of fluorescence signals that were ultimately focused on WSNs, target miRNAs could be sensitively identified to a femtomolar level (5 fM) with a wide dynamic range of up to 6 orders of magnitude. The proposed strategy achieved high specificity to obviously distinguish single-base mutation sequences and possessed multiplex assay capability. Moreover, the assay exhibited excellent practicability in the multiplex detection of miRNAs in clinical serum specimens.

Decreased NSD2 impairs stromal cell proliferation in human endometrium via reprogramming H3K36me2.

In brief: The proliferation of the endometrium is regulated by histone methylation. This study shows that decreased NSD2 impairs proliferative-phase endometrial stromal cell proliferation in patients with recurrent implantation failure via epigenetic reprogramming of H3K36me2 methylation on the promoter region of MCM7. Abstract: Recurrent implantation failure (RIF) is a formidable challenge in assisted reproductive technology because of its unclear molecular mechanism. Impaired human endometrial stromal cell (HESC) proliferation disrupts the rhythm of the menstrual cycle, resulting in devastating disorders between the embryo and the endometrium. The molecular function of histone methylation enzymes in modulating HESC proliferation remains largely uncharacterized. Herein, we found that the levels of histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) and the dimethylation of lysine 36 on histone H3 are decreased significantly in the proliferative-phase endometrium of patients with RIF. Knockdown of NSD2 in an HESC cell line markedly impaired cell proliferation and globally reduced H3K36me2 binding to chromatin, leading to altered expression of many genes. Transcriptomic analyses revealed that cell cycle-related gene sets were downregulated in the endometrium of patients with RIF and in NSD2­knockdown HESCs. Furthermore, RNA-sequencing and CUT&Tag sequencing analysis suggested that NSD2 knockdown reduced the binding of H3K36me2 to the promoter region of cell cycle marker gene MCM7 (encoding minichromosome maintenance complex component 7) and downregulated its expression. The interaction of H3K36me2 with the MCM7 promoter was verified using chromatin immunoprecipitation-quantitative real-time PCR. Our results demonstrated a unifying epigenome-scale mechanism by which decreased NSD2 impairs endometrial stromal cell proliferation in the proliferative-phase endometrium of patients with RIF.

Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.

Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.

Plasma Thioredoxin Reductase as a Potential Biomarker for Gynecologic Cancer.

BACKGROUND: According to previous literatures, plasma thioredoxin reductase (TrxR) level was significantly elevated in various malignant tumors and serve as a potential biomarker for diagnosis and prognostic prediction. However, there is little awareness of the clinical value of plasma TrxR in gynecologic malignancies. In the present study, we aim to evaluate the diagnostic accuracy of plasma TrxR in gynecologic cancer and explore its role in treatment surveillance. METHODS: We retrospectively enrolled 134 patients with gynecologic cancer and 79 patients with benign gynecologic disease. The difference of plasma TrxR activity and tumor markers level between two groups was compared using Mann-Whitney U test. By detecting pretreatment and post-treatment level of TrxR and conventional tumor markers, we further assessed the change trend of them with the Wilcoxon signed-ranks test. RESULTS: Compared with benign control [5.7 (5, 6.6) U/mL], statistically significant increase of TrxR activity was observed in gynecologic cancer group [8.4 (7.25, 9.825) U/mL] (P < .0001), regardless of age and stage. On the basis of receiver operating characteristic (ROC) curves, we found plasma TrxR shows the highest diagnostic efficacy for distinguishing malignancy with benign disease, with an area under the curve (AUC) of 0.823 (95% confidence interval [CI] = 0.767-0.878), in the whole cohort. Besides, patients receiving treatment previously [8 (6.5, 9) U/mL] had a decreased TrxR level relative to treatment-native patients [9.9 (8.6, 10.85) U/mL]. Furthermore, follow-up data showed that plasma TrxR level would be evidently decreased after two courses of antitumor therapy (P < .0001), which is consistent with the downward trend of conventional tumor markers. CONCLUSION: Collectively, all these results demonstrated plasma TrxR is an effective parameter for gynecologic cancer diagnosis and concurrently acts as a promising biomarker for treatment response assessment.

Stromal cell-derived small extracellular vesicles enhance radioresistance of prostate cancer cells via interleukin-8-induced autophagy.

Radiation is a curative treatment for localized prostate cancer (PCa). Unfortunately, radiotherapeutic efficacy is often diminished when patients develop more aggressive or metastatic phenotypes. Recent studies have demonstrated that extracellular vesicles participate in cancer therapeutic resistance by delivering small bioactive molecules, such as small non-coding RNAs. Here, we show that stromal cell-derived small extracellular vesicles (sEVs) facilitate the radioresistance of PCa cells by transporting interleukin-8 (IL-8). Indeed, prostatic stromal cells secrete more IL-8 than AR-positive PCa cells, which can be accumulated in sEVs. Intriguingly, the uptake of stromal cells-derived sEVs by radiosensitive PCa cells enhanced their radioresistance, which could be attenuated by silencing CXCL8 in stromal cells or inhibiting its receptor CXCR2 in PCa cells. sEV-mediated radioresistance has been validated in zebrafish and mouse xenograft tumours. Mechanistically, the uptake of stromal sEVs triggers the AMPK-activated autophagy pathway in PCa cells under the irradiation condition. Consequently, inactivating AMPK efficiently resensitized radiotherapy either by utilizing an AMPK inhibitor or silencing AMPKα in PCa cells. Furthermore, chloroquine (CQ), a lysosomal inhibitor, sufficiently resensitized radiotherapy via blockade of autophagolysosome fusion, leading to autophagosome accumulation in PC cells. Collectively, these results suggest that stromal cells enhance the radioresistance of PCa cells mainly through sEVs that deliver IL-8.

Thioredoxin reductase as a novel biomarker for the diagnosis and efficacy prediction of gastrointestinal malignancy: a large-scale, retrospective study.

BACKGROUND: Our aim was to investigate the rationality and accuracy of plasma TrxR activity as an efficient tool in the early diagnosis of gastrointestinal malignancy, and whether TrxR can be used to evaluate the therapeutic efficacy of gastrointestinal malignancy. METHODS: We enrolled a total of 5091 cases, including 3736 cases in gastrointestinal malignancy, 964 in benign diseases, and 391 cases in healthy controls. We also performed receiver operating characteristic (ROC) analysis to evaluate diagnostic efficiency of TrxR. Finally, we detected pre- and post-treatment level of TrxR and common tumor markers. RESULTS: The plasma TrxR level in patients with gastrointestinal malignancy [8.4 (6.9, 9.7) U/mL] was higher than that in patients with benign disease [5.8 (4.6, 6.9) U/mL] and healthy control [3.5 (1.4, 5.4) U/mL]. Plasma TrxR showed a significant diagnostic advantage with an AUC of 0.897, compared with conventional tumor markers. In addition, the combination of TrxR and conventional tumor markers can further improve the diagnostic efficiency. We derived the optimal cut-off value of plasma TrxR as a diagnostic marker of gastrointestinal malignancy according to Youden index of 6.15 U/mL. After measuring the change trend of TrxR activity and conventional tumor markers before and after anti-tumor treatments, we found that their change trend was generally consistent, and the plasma TrxR activity was significantly decreased in patients treated with chemotherapy, targeted therapy and immunotherapy. CONCLUSIONS: Our findings recommend that plasma TrxR activity could be monitored as an efficient tool for the early diagnosis of gastrointestinal malignancy and as a feasible tool to evaluate the therapeutic effect.

Human Nanoplatelets as Living Vehicles for Tumor-Targeted Endocytosis In Vitro and Imaging In Vivo.

Recent studies have shown human platelets can access the tumor microenvironment by passive diffusion across capillaries or via activated immune cells. In a previous study, we exploited this affinity of platelets for tumor cells as part of a new approach to target tumors with modified platelets. Therefore, the engineering of human nanoplatelets as living vehicles for in vivo tumor-targeted near-infra-red fluorescence (NIRF) imaging and the delivery of cytotoxins to tumor cells by endocytosis are described in this study. Nanoplatelets with an average diameter of 200 nm were prepared by mild sonication of kabiramide C (KabC)-loaded human platelets. The sealed plasma membrane of the nanoplatelets allows them to accumulate and retain membrane-permeable chemicals, such as epidoxorubicin (EPI) and KabC. Tumor-targeted imaging functionalities were engineered on the nanoplatelets by surface-coupling transferrin, Cy5 and Cy7. High-resolution fluorescence imaging and flow cytometry analyses showed that the nanoplatelets loaded with EPI and Cy5 targeted human myeloma cells (RPMI8226 cells) that over-expressed the transferrin receptor. The endocytosis of the nanoplatelets by RPMI8226 cells was transferrin-dependent and induced apoptosis. The test results also showed that the nanoplatelets functionalized with transferrin and Cy7 and injected in mice bearing RPMI8226 cells-derived myeloma xenotransplants accumulated in the tumor tissue and could be used for high-contrast in vivo NIRF imaging of early-stage tumors. Nanoplatelets represent a new class of living nano-vehicles that may efficiently target and deliver therapeutic agents and imaging probes to diseased tissues including tumors.

Intra-amniotic mesenchymal stem cell therapy improves the amniotic fluid microenvironment in rat spina bifida aperta fetuses.

OBJECTIVES: Spina bifida aperta (SBA) is one of the most common neural tube defects. Neural injury in SBA occurs in two stages involving failed neural tube closure and progressive degeneration through contact with the amniotic fluid. We previously suggested that intra-amniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for fetal rat SBA could achieve beneficial functional recovery through lesion-specific differentiation. The aim of this study is to examine whether the amniotic fluid microenvironment can be improved by intra-amniotic BMSC transplantation. METHODS: The intra-amniotic BMSC injection was performed using in vivo rat fetal SBA models. The various cytokine expressions in rat amniotic fluid were screened by protein microassays. Intervention experiments were used to study the function of differentially expressed cytokines. RESULTS: A total of 32 cytokines showed significant upregulated expression in the BMSC-injected amniotic fluid. We focused on Activin A, NGF, BDNF, CNTF, and CXCR4. Intervention experiments showed that the upregulated Activin A, NGF, BDNF, and CNTF could inhibit apoptosis and promote synaptic development in fetal spinal cords. Inhibiting the activity of these factors weakened the anti-apoptotic and pro-differentiation effects of transplanted BMSCs. Inhibition of CXCR4 activity reduced the engraftment rate of BMSCs in SBA fetuses. CONCLUSION: BMSC transplantation can improve the amniotic fluid environment, and this is beneficial for SBA repair.

The biological functions and related signaling pathways of SPON2.

Spondin-2 (SPON2), also referred to as M-spondin or DIL-1, is a member of the extracellular matrix protein family known as Mindin-F-spondin (FS). SPON2 can be used as a broad-spectrum tumor marker for more than a dozen tumors, mainly prostate cancer. Meanwhile, SPON2 is also a potential biomarker for the diagnosis of certain non-tumor diseases. Additionally, SPON2 plays a pivotal role in regulating tumor metastasis and progression. In normal tissues, SPON2 has a variety of biological functions represented by promoting growth and development and cell proliferation. This paper presents a comprehensive overview of the regulatory mechanisms, diagnostic potential as a broad-spectrum biomarker, diverse biological functions, involvement in various signaling pathways, and clinical applications of SPON2.

Noninvasive Multiplexed Analysis of Bladder Cancer-Derived Urine Exosomes via Janus Magnetic Microspheres.

Bladder cancer greatly endangers human health, and its early diagnosis is of vital importance. Exosomes, which contain proteins and nucleic acids related to their source cells, are expected to be an emerging biomarker for bladder cancer detection. Here, we propose a novel system for multiplexed analysis of bladder cancer-derived urine exosomes based on Janus magnetic microspheres as barcoded microcarriers. The microcarriers are constructed by droplet-templated coassembly of colloidal silica nanoparticles and magnetic nanoparticles under a magnetic field. The microcarriers possess one hemisphere with structural color and the other hemisphere with magneto-responsiveness. Benefiting from the unique structure, these Janus microcarriers could serve as barcodes and could move controllably in a sample solution, thus realizing the multiplex detection of exosomes with high sensitivity. Notably, the present platform is noninvasive since a urine specimen, as an ideal source of bladder cancer-derived exosomes, is employed as the sample solution. This feature, together with the good sensitivity, specificity, low sample consumption, and easy operation, indicates the great potential of the platform for bladder cancer diagnosis in clinical applications.

The Prognosis of Diabetic Foot Ulcer is Independent of age? A Comparative Analysis of the Characteristics of Patients with Diabetic Foot Ulcer in Different age Groups: A Cross-Sectional Study from China.

Background: With younger onset age of type 2 diabetes mellitus (T2DM), the incidence of diabetic foot ulcer (DFU) in young and middle-aged adults is also increasing. Elucidating the distinctive characteristics of DFU in different ages and exploring the influence of age on the prognosis of DFU are crucial to the improvement of DFU treatments. Methods: 684 patients hospitalized for DFU in the department of endocrinology were recruited and assigned into the young and middle-aged group (age <65 years old) and the elderly group (age ≥65 years old). Demographic data and clinical features were compared between two groups. Results: Compared with the elderly group, the young and middle-aged group had higher proportion of males (72.3% vs 49.6%, P < .01) and smokers (52.5% vs 35.8%, P < .01), shorter duration of diabetes mellitus (155 months vs 196 months, P < .01), higher levels of glycosylated hemoglobin (9.3% vs 8.7%, P < .01), lower ratio of ankle-brachial index <0.9 (25.8% vs 51.1%, P < .01) and higher levels of c-reactive protein and erythrocyte sedimentation rate (14 mg/L vs 10 mg/L, P < .05; 36 mm/h vs 30 mm/h, P < .05). The prevalence of diabetic peripheral neuropathy and Wagner Grade were similar in two groups. Of note, the prognosis was similar in different age groups, as there were no significant differences in the healing rate (59.7% vs 60.1%, P > .05), healing time (30 days vs 22 days, P > .05) and minor amputation rate (11.9% vs 8.7%, P > .05). Conclusions: We found that no evidence to suggest a better prognosis with younger DFU patients. Compared with elderly ones, young and middle-aged patients were characterized by a higher proportion of smoking, worse glycemic control, higher inflammatory biomarkers but less severe lower limb ischemia, indicating that smoking cessation, strict blood glucose control and early detection of infection were crucial for improving the prognosis of young and middle-aged diabetic DFU patients.

Disitamab vedotin, a novel HER2-directed antibody-drug conjugate in gastric cancer and other solid tumors.

Antibody-drug conjugates (ADC), a combination of cytotoxic drugs and antibodies, have emerged as a rising star in cancer therapy. Disitamab vedotin (RC48), a novel ADC targeting human epidermal growth factor receptor 2 (HER2), is currently being explored in a variety of malignancies. Compared with conventional HER2-targeting agents, RC48 is characterized by a wider therapeutic window and less toxicity to normal tissues. In this review, we will analyze the structural elements and mechanisms of RC48. Besides, we provide a landscape on the progression of RC48 in common malignancies, focusing on RC48 in gastric or gastroesophageal junction cancer, and a brief overview of urothelial, breast and other cancers (e.g., gynecological cancer, biliary tract cancer, non-small cell lung cancer and myometrial invasive bladder cancer). Finally, we will also discuss future challenges in the development of RC48 and future directions to improve efficacy.

Pollen-Inspired Photonic Barcodes with Prickly Surface for Multiplex Exosome Capturing and Screening.

Exosomes, which play an important role in intercellular communication, are closely related to the pathogenesis of disease. However, their effective capture and multiplex screening are still challenging. Here, inspired by the unique structure of pollens, we present novel photonic crystal (PhC) barcodes with prickly surface by hydrothermal synthesis for multiplex exosome capturing and screening. These pollen-inspired PhC barcodes are imparted with extremely high specific surface area and excellent prickly surface nanostructures, which can improve the capture rate and detection sensitivity of exosomes. As the internal periodic structures are kept during the hydrothermal synthesis process, the pollen-inspired PhC barcodes exhibit obvious and stable structural colors for identification, which enables multiplex detection of exosomes. Thus, the pollen-inspired PhC barcodes can not only effectively capture and enrich cancer-related exosomes but also support multiplex screening of exosomes with high sensitivity. These features make the prickly PhC barcodes ideal for the analysis of exosomes in medical diagnosis.

Serum exosomal coronin 1A and dynamin 2 as neural tube defect biomarkers.

No highly specific and sensitive biomarkers have been identified for early diagnosis of neural tube defects (NTDs). In this study, we used proteomics to identify novel proteins specific for NTDs. Our findings revealed three proteins showing differential expression during fetal development. In a rat model of NTDs, we used western blotting to quantify proteins in maternal serum exosomes on gestational days E18, E16, E14, and E12, in serum on E18 and E12, in neural tubes on E18 and E12, and in fetal neural exosomes on E18. The expression of coronin 1A and dynamin 2 was exosome-specific and associated with spina bifida aperta embryogenesis. Furthermore, coronin 1A and dynamin 2 were significantly downregulated in maternal serum exosomes (E12-E18), neural tubes, and fetal neural exosomes. Although downregulation was also observed in serum, the difference was not significant. Differentially expressed proteins were further analyzed in the serum exosomes of pregnant women during gestational weeks 12-40 using enzyme-linked immunosorbent assays. The findings revealed that coronin 1A and dynamin 2 showed potential diagnostic efficacy during gestational weeks 12-40, particularly during early gestation (12-18 weeks). Therefore, these two targets are used as candidate NTD screening and diagnostic biomarkers during early gestation. KEY MESSAGES: We used proteomics to identify novel proteins specific for NTDs. CORO1A and DNM2 showed exosome-specific expression and were associated with SBA. CORO1A and DNM2 were downregulated in maternal serum exosomes and FNEs. CORO1A and DNM2 showed good diagnostic efficacy for NTDs during early gestation. These two targets may have applications as NTD screening and diagnostic biomarkers.

Intra-amniotic transplantation of brain-derived neurotrophic factor-modified mesenchymal stem cells treatment for rat fetuses with spina bifida aperta.

BACKGROUND: Spina bifida aperta (SBA) is a relatively common clinical type of neural tube defect. Although prenatal fetal surgery has been proven to be an effective treatment for SBA, the recovery of neurological function remains unsatisfactory due to neuron deficiencies. Our previous results demonstrated that intra-amniotic transplanted bone marrow mesenchymal stem cells (BMSCs) could preserve neural function through lesion-specific engraftment and regeneration. To further optimize the role of BMSCs and improve the environment of defective spinal cords so as to make it more conducive to nerve repair, the intra-amniotic transplanted BMSCs were modified with brain-derived neurotrophic factor (BDNF-BMSCs), and the therapeutic potential of BDNF-BMSCs was verified in this study. METHODS: BMSCs were modified by adenovirus encoding a green fluorescent protein and brain-derived neurotrophic factor (Ad-GFP-BDNF) in vitro and then transplanted into the amniotic cavity of rat fetuses with spina bifida aperta which were induced by all-trans-retinoic acid on embryonic day 15. Immunofluorescence, western blot and real-time quantitative PCR were used to detect the expression of different neuron markers and apoptosis-related genes in the defective spinal cords. Lesion areas of the rat fetuses with spina bifida aperta were measured on embryonic day 20. The microenvironment changes after intra-amniotic BDNF-BMSCs transplantation were investigated by a protein array with 90 cytokines. RESULTS: We found that BDNF-BMSCs sustained the characteristic of directional migration, engrafted at the SBA lesion area, increased the expression of BDNF in the defective spinal cords, alleviated the apoptosis of spinal cord cells, differentiated into neurons and skin-like cells, reduced the area of skin lesions, and improved the amniotic fluid microenvironment. Moreover, the BDNF-modified BMSCs showed a better effect than pure BMSCs on the inhibition of apoptosis and promotion of neural differentiation. CONCLUSION: These findings collectively indicate that intra-amniotic transplanted BDNF-BMSCs have an advantage of promoting the recovery of defective neural tissue of SBA fetuses.

Tumorigenic cell selection and substrate rigidity manipulation using 2D and 3D extracellular matrices.

Soft fibrin gels are used to select tumorigenic cells and regulate the stemness and metastasis of colorectal cancer cells via mechanotransduction. This protocol details steps to produce two-dimensional (2D) and three-dimensional (3D) extracellular matrices for substrate rigidity manipulation and tumorigenic cell selection. We also describe how it can be applied to tumor mechanotransductive research by colony growth monitoring and cell isolation. For complete details on the use and execution of this protocol, please refer to Chang et al. (2022).

Plasma thioredoxin reductase: a potential diagnostic biomarker for gastric cancer.

To improve the early detection of gastric cancer (GC), there is a growing need for novel and efficient biomarkers. We aimed to evaluate diagnostic value of thioredoxin reductase 1 (TXNRD1), which was found to be over expressed in various malignancies. We found that TXNRD1 has a higher expression level in GC tissues compared with adjacent normal tissues, and high TXNRD1 expression was significantly associated with poor outcomes of GC patients. Next, a total of 1446 cases were collected, with 896 cases in GC, 322 in benign gastric disease and 228 in healthy controls. We noticed plasma thioredoxin reductase (TrxR) level in GC [8.4 (7.1, 9.7) U/ml] was significantly higher than that in benign disease [6.1 (5.4, 7.2) U/ml] or healthy controls [3.7 (1.7, 5.6) U/ml]. Receiver operating characteristic analysis showed that the optimal cutoff value of TrxR activity for GC diagnosis was set at 5.75 U/ml with an area under the curve of 0.945. Moreover, a combined panel of TrxR and routine tumor markers could further elevate the diagnostic efficacy compared to a single biomarker. Finally, by measuring pre- and post-treatment TrxR activity and routine tumor markers, we found the change trend of them was broadly consistent, and plasma TrxR activity was significantly decreased in patients treated with platinum/fluorouracil-based therapy. Our findings recommend plasma TrxR activity combined with tumor markers as effective diagnostic tools for GC patients. As well, plasma TrxR has the potential to monitor therapeutic efficacy.

METTL3-Mediated ADAMTS9 Suppression Facilitates Angiogenesis and Carcinogenesis in Gastric Cancer.

The role of methyltransferase-like 3 (METTL3), which participates in catalyzing N-methyladenosine (m6A) RNA modification, in gastric cancer (GC) is unclear. Here, we found that METTL3 was overexpressed in human GC. Functionally, we verified that METTL3 promoted tumor cell proliferation and angiogenesis through a series of phenotypic experiments. Subsequently, ADAMTS9 was identified as the downstream effector of METTL3 in GC, which could be degraded by the YTHDF2-dependent pathway. Finally, the data suggested that METTL3 might facilitate GC progression through the ADAMTS9-mediated PI3K/AKT pathway. Our study unveiled the fundamental mechanisms of METTL3 in GC progression. The clinical value of METTL3 in GC deserves further exploration.