The Role of CXCL11 and its Receptors in Cancer: Prospective but Challenging Clinical Targets.

Chemokine ligand 11 is a member of the CXC chemokine family and exerts its biological function mainly through binding to CXCR3 and CXCR7. The CXCL11 gene is ubiquitously overexpressed in various human malignant tumors; however, its specific mechanisms vary among different cancer types. Recent studies have found that CXCL11 is involved in the activation of multiple oncogenic signaling pathways and is closely related to tumorigenesis, progression, chemotherapy tolerance, immunotherapy efficacy, and poor prognosis. Depending on the specific expression of its receptor subtype, CXCL11 also has a complex 2-fold role in tumours; therefore, directly targeting the structure-function of CXCL11 and its receptors may be a challenging task. In this review, we summarize the biological functions of CXCL11 and its receptors and their roles in various types of malignant tumors and point out the directions for clinical applications.

CXCL11 is found in many types of cancer and affects how cancer cells grow and respond to treatments. This paper delves into the intricate dance between CXCL11 and its receptors in various types of cancer. Like a versatile actor playing different roles on stage, CXCL11 can either promote or hinder cancer growth depending on its interaction with specific receptors. Understanding how CXCL11 works could help develop new treatments for cancer, but it's a complex challenge because CXCL11 can have different effects depending on the type of cancer and which receptors it binds to.

Differentiation of Native Vertebral Osteomyelitis: A Comprehensive Review of Imaging Techniques and Future Applications.

Native vertebral osteomyelitis, also termed spondylodiscitis, is an antibiotic-resistant disease that requires long-term treatment. Without proper treatment, NVO can lead to severe nerve damage or even death. Therefore, it is important to accurately diagnose the cause of NVO, especially in spontaneous cases. Infectious NVO is characterized by the involvement of 2 adjacent vertebrae and intervertebral discs, and common infectious agents include Staphylococcus aureus, Mycobacterium tuberculosis, Brucella abortus, and fungi. Clinical symptoms are generally nonspecific, and early diagnosis and appropriate treatment can prevent irreversible sequelae. Advances in pathologic histologic imaging have led physicians to look more forward to being able to differentiate between tuberculous and septic spinal discitis. Therefore, research in identifying and differentiating the imaging features of these 4 common NVOs is essential. Due to the diagnostic difficulties, clinical and radiologic diagnosis is the mainstay of provisional diagnosis. With the advent of the big data era and the emergence of convolutional neural network algorithms for deep learning, the application of artificial intelligence (AI) technology in orthopedic imaging diagnosis has gradually increased. AI can assist physicians in imaging review, effectively reduce the workload of physicians, and improve diagnostic accuracy. Therefore, it is necessary to present the latest clinical research on NVO and the outlook for future AI applications.

Auricular Vagal Nerve Stimulation Inhibited Central Nerve Growth Factor/Tropomyosin Receptor Kinase A/Phospholipase C-Gamma Signaling Pathway in Functional Dyspepsia Model Rats With Gastric Hypersensitivity.

OBJECTIVE: Functional dyspepsia (FD), which has a complicated pathophysiologic process, is a common functional gastrointestinal disease. Gastric hypersensitivity is the key pathophysiological factor in patients with FD with chronic visceral pain. Auricular vagal nerve stimulation (AVNS) has the therapeutic effect of reducing gastric hypersensitivity by regulating the activity of the vagus nerve. However, the potential molecular mechanism is still unclear. Therefore, we investigated the effects of AVNS on the brain-gut axis through the central nerve growth factor (NGF)/ tropomyosin receptor kinase A (TrkA)/phospholipase C-gamma (PLC-γ) signaling pathway in FD model rats with gastric hypersensitivity. MATERIALS AND METHODS: We established the FD model rats with gastric hypersensitivity by means of colon administration of trinitrobenzenesulfonic acid on ten-day-old rat pups, whereas the control rats were given normal saline. AVNS, sham AVNS, K252a (an inhibitor of TrkA, intraperitoneally), and K252a + AVNS were performed on eight-week-old model rats for five consecutive days. The therapeutic effect of AVNS on gastric hypersensitivity was determined by the measurement of abdominal withdrawal reflex response to gastric distention. NGF in gastric fundus and NGF, TrkA, PLC-γ, and transient receptor potential vanilloid 1 (TRPV1) in the nucleus tractus solitaries (NTS) were detected separately by polymerase chain reaction, Western blot, and immunofluorescence tests. RESULTS: It was found that a high level of NGF in gastric fundus and an upregulation of the NGF/TrkA/PLC-γ signaling pathway in NTS were manifested in model rats. Meanwhile, both AVNS treatment and the administration of K252a not only decreased NGF messenger ribonucleic acid (mRNA) and protein expressions in gastric fundus but also reduced the mRNA expressions of NGF, TrkA, PLC-γ, and TRPV1 and inhibited the protein levels and hyperactive phosphorylation of TrkA/PLC-γ in NTS. In addition, the expressions of NGF and TrkA proteins in NTS were decreased significantly after the immunofluorescence assay. The K252a + AVNS treatment exerted a more sensitive effect on regulating the molecular expressions of the signal pathway than did the K252a treatment. CONCLUSION: AVNS can regulate the brain-gut axis effectively through the central NGF/TrkA/PLC-γ signaling pathway in the NTS, which suggests a potential molecular mechanism of AVNS in ameliorating visceral hypersensitivity in FD model rats.

A prediction model for sulcus-to-sulcus diameter in myopic eyes: a 1466-sample retrospective study.

BACKGROUND: To establish and verify the accuracy and reliability of a sulcus-to-sulcus diameter (STS) prediction model. METHODS: In this retrospective study, the prediction formula was established with the data from 1466 eyes from 733 subjects from July 2020 to April 2021 and verified with the data from 278 eyes from 139 subjects between May 2021 and June 2021. Each subject was measured with a Pentacam, IOLMaster 700, OPD-Scan III, and ultrasound biomicroscope. The prediction formulas were established with multiple linear regression, and intergroup correlation coefficients (ICCs) and Bland-Altman tests were used to assess the agreement between the predicted and actual STS (actual STS was measured by UBM). RESULTS: The explanatory variables relevant to the horizontal STS (STSH) were the Pentacam white-to-white diameter (WTWP; standardized partial regression coefficient [ß] = 0.330; p < 0.001), the flat K value (ß = -0.211; p < 0.001), and the anterior corneal diameter (ACD) (ß = 0.178; p < 0.001). The corresponding multiple regression equation was : STSH (mm) = 8.061 + 0.510 × WTWP - 0.090 × Flat K value + 0.430 × ACD. The explanatory variables relevant to the vertical STS (STSV) were the WTWP (ß = 0.435; p < 0.001), the steep K value (ß = -0.271; p < 0.001), and the ACD (ß = 0.187; p < 0.001). The corresponding multiple regression equation was : STSV (mm) = 8.540 + 0.492 × WTWP - 0.075 × Steep K value + 0.329 × ACD. The bias of the predicted to the actual STSH was - 0.021, with 95% limits of agreement (95% LoA) from - 0.499 to 0.457. The bias of the predicted to the actual STSV was 0.057, with 95% LoA from - 0.462 to 0.575. The ICC was 0.883 between the predicted and actual STSH and 0.859 between the predicted and actual STSV. CONCLUSIONS: The Pentacam-measured WTW, the K value and the ACD are important for predicting the STS diameter. The prediction model has good accuracy and reliability. TRIAL REGISTRATION: Not applicable.

MiR-34c promotes hepatic stellate cell activation and Liver Fibrogenesis by suppressing ACSL1 expression.

Normally, there are multiple microRNAs involved in the pathogenesis of liver fibrosis. In our work, we aimed at identifying the role of miR-34c in the hepatic stellate cell (HSC) activation and liver fibrosis and its potential mechanism. Our results have shown that during natural activation of HSC, the level of miR-34c was increased significantly whereas acyl-CoA synthetase long-chain family member-1(ACSL1), which is a key enzyme can affect fatty acid(FA) synthesis, was decreased. A double fluorescence reporter assay further confirmed that ACSL1 is a direct target gene of miR-34c. Moreover, the inhibition of miR-34C can attenuate the synthesis of collagen in HSC-T6. In our rescue assay, ACSL1 expression was 1.49-fold higher compared to normal control cells which were transfected with the miR-34c inhibitor in a stable low expression ACSL1 cell line. While at the same time, α-SMA and Col1α expression decreased by 18.22% and 2.58%, respectively. Moreover, we performed an in vivo model using dimethylnitrosamine (DMN) in conjunction with the miR-34c agomir, combined with the treatment of DMN and the miR-34c agomir can increase liver fibrosis. Meanwhile, the degree of hepatic fibrosis was increased and lipid droplets reduced dramatically in rats and HSC-T6 cell treated with miR-34c mimics alone compared to untreated groups. Our results indicate that miR-34c plays an essential role in liver fibrosis by targeting ACSL1 closely associated with lipid droplets, and it might be used as a potential therapeutic target.

Short-term changes in and preoperative factors affecting vaulting after posterior chamber phakic Implantable Collamer Lens implantation.

BACKGROUND: To describe the very early vault changes in the first month after Implantable Collamer Lens (ICL) implantation and to evaluate the effect of preoperative biometric factors on vault. METHODS: Eighty-three eyes from eighty-three subjects with complete data who met follow-up requirements were recruited in this retrospective study between May 2019 and March 2020. We quantitatively assessed the postoperative vault at 2 h, 1 day, 1 week, and 1 month following implantation. Associations between the postoperative vault and age, ICL size, spherical equivalent (SE), axial length (AL), central corneal thickness (CCT), flat keratometry (K), steep K, mean K, anterior chamber depth (ACD), crystalline lens thickness (LT), white-to-white (WTW) diameter obtained by three devices, horizontal and vertical sulcus-to-sulcus (STS) diameter, bright and dark pupil sizes (BPS and DPS) and DPS-BPS were investigated using Spearman's correlation analysis and stepwise multiple regression analysis. RESULTS: The mean vault values at 2 h, 1 day, 1 week, and 1 month after ICL implantation were 672.05 ± 30.72, 389.15 ± 28.33, 517.23 ± 30.76 and 530.12 ± 30.22 µm, respectively. Significant differences were found in the vault values at 2 h, 1 day and 1 week after the operation. The ICL size (ß = 0.942; p < 0.001), followed by horizontal STS (ß = -0.517; p < 0.001), crystalline LT (ß = -0.376; p < 0.001) and vertical STS (ß = -0.257; p = 0.017), significantly influenced the vault at 1 month after the operation. The multiple regression equation was expressed as follows: central vault (µm) = -1369.05 + 657.121 × ICL size- 287.408 × horizontal STS - 432.497 × crystalline LT - 137.33 × vertical STS (adjusted R2 = 0.643). CONCLUSIONS: After ICL implantation, the vault decreased and then increased, but it did not return to the vault value 2 h after surgery. The ICL size, horizontal and vertical STS and crystalline LT are key factors for predicting postoperative vaulting.

Deubiquitinase inhibitor degrasyn suppresses metastasis by targeting USP5-WT1-E-cadherin signalling pathway in pancreatic ductal adenocarcinoma.

Wilm's tumour-1 (WT1) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and enhances metastasis. Deubiquitination stabilizes target proteins, and inhibiting deubiquitination facilitates the degradation of target proteins. However, whether inhibiting deubiquitination of WT1 facilitates its degradation and presents anti-cancer ability in PDAC is unknown. Here, we found that deubiquitinase inhibitor degrasyn rapidly induced the degradation of endogenous and exogenous WT1 through enhancing ubiquitination of WT1 followed by the up-regulation of E-cadherin. Knockdown of WT1 by short hairpin RNAs (shRNAs) inhibited metastasis and overexpression of WT1 partially prevented degrasyn-induced anti-metastasis activity, suggesting that degrasyn presents anti-metastasis activity partially through degrading WT1 protein. We further identified that USP5 deubiquitinated WT1 and stabilized its expression. The higher expressions of USP5 and WT1 are associated with tumour metastasis. More importantly, degrasyn inhibited the activity of USP5 and overexpression of USP5 partially prevented degrasyn-induced degradation of WT1 protein, suggesting that degrasyn degraded WT1 protein through inhibiting the activity of USP5. Finally, degrasyn reduced the tumorigenicity in a xenograft mouse model and reduced the metastasis in vivo. Our results indicate that degrasyn presents strong anti-cancer activity through USP5-WT1-E-cadherin signalling in PDAC. Therefore, degrasyn holds promise as cancer therapeutic agent in PDAC with high expressions of USP5 and WT1.

WT1 facilitates the self-renewal of leukemia-initiating cells through the upregulation of BCL2L2: WT1-BCL2L2 axis as a new acute myeloid leukemia therapy target.

BACKGROUND: Overexpression of Wilms' tumor-1 (WT1) transcription factor facilitates proliferation in acute myeloid leukemia (AML). However, whether WT1 is enriched in the leukemia-initiating cells (LICs) and leukemia stem cells (LSCs) and facilitates the self-renewal of LSCs remains poorly understood. METHODS: MLL-AF9-induced murine leukemia model was used to evaluate the effect of knockdown of wt1 on the self-renewal ability of LSC. RNA sequencing was performed on WT1-overexpressing cells to select WT1 targets. Apoptosis and colony formation assays were used to assess the anti-leukemic potential of a deubiquitinase inhibitor WP1130. Furthermore, NOD/SCID-IL2Rγ (NSG) AML xenotransplantation and MLL-AF9-induced murine leukemia models were used to evaluate the anti-leukemogenic potential of WP1130 in vivo. RESULTS: We found that wt1 is highly expressed in LICs and LSCs and facilitates the maintenance of leukemia in a murine MLL-AF9-induced model of AML. WT1 enhanced the self-renewal of LSC by increasing the expression of BCL2L2, a member of B cell lymphoma 2 (BCL2) family, by direct binding to its promoter region. Loss of WT1 impaired self-renewal ability in LSC and delayed the progression of leukemia. WP1130 was found to modify the WT1-BCL2L2 axis, and WP1130-induced anti-leukemic activity was mediated by ubiquitin proteasome-mediated destruction of WT1 protein. WP1130 induced apoptosis and decreased colony formation abilities of leukemia cells and prolonged the overall survival in the THP1-based xenograft NSG mouse model. WP1130 also decreased the frequency of LSC and prolonged the overall survival in MLL-AF9-induced murine leukemia model. Mechanistically, WP1130 induced the degradation of WT1 by positively affecting the ubiquitination of WT1 protein. CONCLUSIONS: Our results indicate that WT1 is required for the development of AML. WP1130 exhibits anti-leukemic activity by inhibiting the WT1-BCL2L2 axis, which may represent a new acute myeloid leukemia therapy target.

Thalidomide induces haematologic responses in patients with ß-thalassaemia.

OBJECTIVE: This study aimed to evaluate the clinical and laboratory outcomes of a group of patients with ß-thalassaemia major or intermedia treated with thalidomide. METHODS: Clinical and laboratory data were obtained by analysing medical records of ß-thalassaemia patients. Using the self-control method, the levels of haemoglobin (Hb), foetal haemoglobin (HbF), white blood cells (WBC) and platelets were detected before and after the treatment, and adverse reactions were recorded. RESULTS: Data from the medical records of 9 patients were analysed. The median haemoglobin levels of these patients increased from 5.13 ± 2.15 g/dL before treatment to 10.38 ± 1.19 g/dL after treatment. The average spleen size decreased from a pretreatment length of 8.19 ± 3.10 to 5.49 ± 1.80 cm below the costal margin after treatment. The mean HbF levels increased from a pretreatment value of 35.67% ± 26.82% to 75.67% ± 14.64% after treatment in the 9 patients for whom these measurements were available. All patients no longer needed transfusions by 1 month after treatment. No serious adverse reactions were observed in any of the thalidomide-treated patients. CONCLUSION: In this study, thalidomide showed an outstanding effect on ß-thalassaemia patients who required frequent red-cell transfusions. Thalidomide increased haemoglobin levels without causing serious adverse reactions, but the long-term curative outcomes and other side effects should be observed continuously.

Microbes for lung cancer detection: feasibility and limitations.

As the second most common cancer in the world, the development of lung cancer is closely related to factors such as heredity, environmental exposure, and lung microenvironment, etc. Early screening and diagnosis of lung cancer can be helpful for the treatment of patients. Currently, CT screening and histopathologic biopsy are widely used in the clinical detection of lung cancer, but they have many disadvantages such as false positives and invasive operations. Microbes are another genome of the human body, which has recently been shown to be closely related to chronic inflammatory, metabolic processes in the host. At the same time, they are important players in cancer development, progression, treatment, and prognosis. The use of microbes for cancer therapy has been extensively studied, however, the diagnostic role of microbes is still unclear. This review aims to summarize recent research on using microbes for lung cancer detection and present the current shortcomings of microbes in collection and detection. Finally, it also looks ahead to the clinical benefits that may accrue to patients in the future about screening and early detection.

Using multiomics to explore the weight differences between genders in Muscovy ducks.

Sexual dimorphism in poultry, especially in Muscovy ducks, is a proven phenomenon characterized by significant differences in body weight, growth patterns, and gene expression between male and female individuals. However, there is a dearth of research on the candidate genes and mechanisms underlying these weight differences. We selected 301 Muscovy ducks and recorded their weekly body weights from birth. We utilized 3 non-linear growth models (Logistic, Bertalanffy, and Gompertz) to fit the growth curve of Muscovy ducks, it was found that the logistic model was the most suitable model for describing the growth curve of Muscovy ducks. The results from the logistic model showed that the inflection point of male Muscovy ducks occurred at a later age, and they had a heavier mature body weight than female Muscovy ducks. At 10 wk of age, we collected Muscovy duck breast muscle tissues for transcriptome sequencing (RNA-seq). To exclude the impact of weight difference, 185 differentially expressed genes (DEGs), such as PPAR, FABP3, PLIN1, and FOXO1, were screened. These DEGs were predominantly enriched in terms related to mitochondria, lipids, and nucleic acids. In addition, the gut microbiota has the ability to influence host physiology through the regulation of multiple processes, including playing a crucial role in host muscle growth and development. We randomly selected male and female Muscovy ducks for 16S rRNA sequencing analysis of their cecal microbiota. The results showed that there were significant differences in the composition of cecal microbiota between male and female Muscovy ducks. At the genus level, the relative abundance of Enterenecus and CAG_269 were lower in males compared to females, while Lawsonibacter, Parabacteroides_B, Streptococcus, UBA2658, Caccousia, and Butyricimonas were higher in males than in females. In summary, this study provides a scientific theoretical basis for revealing the different growth patterns of male and female Muscovy ducks, and offers explanations from both the molecular level and microbiological perspectives.

Erratum: Thioredoxin 1 supports colorectal cancer cell survival and promotes migration and invasion under glucose deprivation through interaction with G6PD: Erratum.

[This corrects the article DOI: 10.7150/ijbs.71809.].

Long-Term Follow-Up of Patients Undergoing Thalidomide Therapy for Transfusion-Dependent ß-Thalassaemia: A Single-Center Experience.

Objective: We evaluated the long-term safety and efficacy of thalidomide in the treatment of transfusion-dependent ß-thalassemia (TDT). Methods: Fifty patients with TDT were treated with thalidomide and followed-up for 5 years. Thalidomide at a 50 mg dose was administered once a day after dinner. The dose was increased to 150 mg/d after 3 d if well tolerated. After 1 year of treatment, the hemoglobin (Hb) level was stabilized at its maximum, and thalidomide was gradually reduced and maintained at the minimum dose. The hematological response, transfusion dependence, and haemolytic indicators were assessed. Results: At 9 month of follow-up, 38 (76%) patients achieved an excellent response, 1 (2%) a good response, 4(8%) a minor response, and 7(14%) did not show a response. The overall response rate was 86%. At 9 months, the Hb level increased from 79.0 ± 13.2 g/L at baseline to 99.0 ± 13.7g/L (P<0.001). Patients who achieved excellent response continued to show an increase in Hb levels during follow-up. At 48 months, the mean Hb level was 98.99 ± 10.3g/L; 21 patients (84.0%) became transfusion independent. Thalidomide was reduced and maintained to 25 mg/d in three of these patients. Moreover, five patients completed 60 months of follow-up, and with a mean Hb level of 99.8 ± 6.7g/L. During follow-up, grade 1-2 adverse drug reactions were noted; however, no grade 3 or higher adverse event was reported. However, no decrease in hemolytic indicators was observed. Conclusion: Thalidomide was well tolerated in the long term, while it significantly improved Hb levels and reduced the transfusion burden.

HMGA2 promotes nasopharyngeal carcinoma progression and is associated with tumor resistance and poor prognosis.

Nasopharyngeal carcinoma (NPC), as one of the most prevalent malignancies in the head and neck region, still lacks a complete understanding of its pathogenesis. Presently, radiotherapy, concurrent chemoradiotherapy, and targeted therapy stand as the primary modalities for treating NPC. With advancements in medicine, the cure rates for nasopharyngeal carcinoma have been steadily increasing. Nevertheless, recurrence and metastasis persist as the primary reasons for treatment failure. Consequently, a profound exploration of the molecular mechanisms underlying the occurrence and progression of nasopharyngeal carcinoma, along with the exploration of corresponding therapeutic approaches, becomes particularly imperative in the quest for comprehensive solutions to combat this disease. High mobility group AT-hook 2 (HMGA2) is a pivotal protein capable of altering chromatin structure, regulating gene expression, and influencing transcriptional activity. In the realm of cancer research, HMGA2 exhibits widespread dysregulation, playing a crucial role in nearly all malignant tumors. It is implicated in various tumorigenic processes, including cell cycle regulation, cell proliferation, epithelial-mesenchymal transition, angiogenesis, tumor invasion, metastasis, and drug resistance. Additionally, HMGA2 serves as a molecular marker and an independent prognostic factor in certain malignancies. Recent studies have increasingly unveiled the critical role of HMGA2 in nasopharyngeal carcinoma (NPC), particularly in promoting malignant progression, correlating with tumor resistance, and serving as an independent adverse prognostic factor. This review focuses on elucidating the oncogenic role of HMGA2 in NPC, suggesting its potential association with chemotherapy resistance in NPC, and proposing its candidacy as an independent factor in nasopharyngeal carcinoma prognosis assessment.

Unbiased and Signal-Weakening Photoelectrochemical Hexavalent Chromium Sensing via a CuO Film Photocathode.

Photoelectrochemical (PEC) sensors show great potential for the detection of heavy metal ions because of their low background noise, high sensitivity, and ease of integration. However, the detection limit is relatively high for hexavalent chromium (Cr(VI)) monitoring in addition to the requirement of an external bias. Herein, a CuO film is readily synthesized as the photoactive material via reactive sputtering and thermal annealing in the construction of a PEC sensing photocathode for Cr(VI) monitoring. A different mechanism (i.e., Signal-Weakening PEC sensing) is confirmed by examining the electrochemical impedance and photocurrent response of different CuO film photoelectrodes prepared with the same conditions in contact with various solutions containing concentration-varying Cr(VI) for different durations. The detection of Cr(VI) is successfully achieved with the Signal-Weakening PEC response; a drop of photocathode signal with an increasing Cr(VI) concentration from the steric hindrance effect of the in situ formed Cr(OH)3 precipitates. The photocurrent of the optimized CuO film photocathode linearly declines as the concentration of Cr(VI) increases from 0.08 to 20 µM, with a detection limit down to 2.8 nM (Signal/Noise = 3) and a fitted sensitivity of 4.22 µA·µM-1. Moreover, this proposed sensing route shows operation simplicity, satisfactory selectivity, and reproducibility.

TAT gene polymorphism and its relationship with production traits in Muscovy ducks (Cairina Moschata).

In a previous study, the laying pattern of Muscovy duck was explored by macro-fitting the laying curve of Muscovy duck, and transcriptome sequencing technique of the ovarian tissues was used to screen the egg-related gene "TAT." Moreover, recent results have shown that TAT is expressed in organs such as oviduct, ovary, and testis. The objective of this study is to examine the effect of TAT gene on egg production traits of Muscovy ducks. First, the expression levels of TAT gene in highest producing (HP) and lowest producing (LP) in 3 tissues related to reproduction were examined, and the results indicated that the expression of TAT gene in hypothalamus was significantly different between HP and LP groups. Then, 6 SNP loci (g. 120G>T, g, 122G>A, g, 254G> A, g. 270C >T, g, 312G>A, and g. 341C>A) were detected in TAT gene. Further, association analysis between the six SNP loci of TAT gene and egg production traits of 652 individual Muscovy ducks was done. The results showed that g. 254G>A and g. 270C>T were significantly correlated (P < 0.05 or 0.001) with the egg production traits of Muscovy ducks. This study elucidated the molecular mechanism that TAT gene might be regulating the egg production traits of Muscovy ducks.

DNA comethylation analysis reveals a functional association between BRCA1 and sperm DNA fragmentation.

OBJECTIVES: To identify the DNA comethylation patterns associated with sperm DNA fragmentation (SDF) and to explore the potential associations of hub genes with SDF. DESIGN: Prospective study. SETTING: University-affiliated reproductive medicine center. PATIENT(S): A total of 300 male patients consulting for couple infertility were recruited from the First Affiliated Hospital of Wenzhou Medical University. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Comethylation network analysis based on the genome-wide methylation profile of spermatozoal DNA from 20 men was performed to identify hub modules and genes involved in SDF. Human spermatozoa were used for targeted bisulfite amplicon sequencing (267 men) or droplet digital polymerase chain reaction (45 men). The potential role of Brca1 in DNA damage was explored in mouse GC2 spermatocyte cells. Oxidative damage to spermatocytes was modeled by incubating GC2 cells with H2O2 (25 mM) for 90 minutes. RESULT(S): BRCA1 was identified as a hub gene in SDF. Promoter hypermethylation of BRCA1 was observed in those samples with a high DNA fragmentation index (DFI) compared to those with a low DFI. Concomitantly, BRCA1 mRNA expression was lower in samples with a high DFI than with a low DFI. In the GC2 cell model, Brca1 knockdown reduced cell proliferation and increased sensitivity to oxidative stress. Moreover, it increased double-strand breaks and decreased the protein levels of the DNA repair genes MRE11 and RAD51. CONCLUSION(S): A prominent cluster of comethylated patterns associated with SDF was identified. BRCA1 may be the hub gene involved in sperm DNA damage.

Thioredoxin 1 supports colorectal cancer cell survival and promotes migration and invasion under glucose deprivation through interaction with G6PD.

Overcoming energy stress is a critical step for cells in solid tumors. Under this stress microenvironment, cancer cells significantly alter their energy metabolism to maintain cell survival and even metastasis. Our previous studies have shown that thioredoxin-1 (Trx-1) expression is increased in colorectal cancer (CRC) and promotes cell proliferation. However, the exact role and mechanism of how Trx-1 is involved in energy stress are still unknown. Here, we observed that glucose deprivation of CRC cells led to cell death and promoted the migration and invasion, accompanied by upregulation of Trx-1. Increased Trx-1 supported CRC cell survival under glucose deprivation. Whereas knockdown of Trx-1 sensitized CRC cells to glucose deprivation-induced cell death and reversed glucose deprivation-induced migration, invasion, and epithelial-mesenchymal transition (EMT). Furthermore, we identified glucose-6-phosphate dehydrogenase (G6PD) interacting with Trx-1 by HuPortTM human protein chip, co-IP and co-localization. Trx-1 promoted G6PD protein expression and activity under glucose deprivation, thereby increasing nicotinamide adenine dinucleotide phosphate (NADPH) generation. Moreover, G6PD knockdown sensitized CRC cells to glucose deprivation-induced cell death and suppressed glucose deprivation-induced migration, invasion, and EMT. Inhibition of Trx-1 and G6PD, together with inhibition of glycolysis using 2-deoxy-D-glucose (2DG), resulted in significant anti-tumor effects in CRC xenografts in vivo. These findings demonstrate a novel mechanism and may represent a new effective therapeutic regimen for CRC.

Research Note: Association of single nucleotide polymorphism of AKT3 with egg production traits in White Muscovy ducks (Cairina moschata).

Prior studies on transcriptomes of hypothalamus and ovary revealed that AKT3 is one of the candidate genes that might affect egg production in White Muscovy ducks. The role of AKT3 in the uterus during reproductive processes cannot be overemphasized. However, functional role of this gene in the tissues and on egg production traits of Muscovy ducks remains unknown. To identify the relationship between AKT3 and egg production traits in ducks, relative expression profile was first examined prior to identifying the variants within AKT3 that may underscore egg production traits [age at first egg (AFE), number of eggs at 300 d (N300D), and number of eggs at 59 wk (N59W)] in 549 ducks. The mRNA expression of AKT3 gene in high producing (HP) ducks was significantly higher than low producing (LP) ducks in the ovary, oviduct, and hypothalamus (P < 0.05 or 0.001). Three variants in AKT3 (C-3631A, C-3766T, and C-3953T) and high linkage block between C-3766T and C-3953T which are significantly (P < 0.05) associated with N300D and N59W were discovered. This study elucidates novel knowledge on the molecular mechanism of AKT3 that might be regulating egg production traits in Muscovy ducks.

Deoxyribonucleic acid methylation signatures in sperm deoxyribonucleic acid fragmentation.

OBJECTIVE: To evaluate Deoxyribonucleic acid (DNA) methylation patterns in sperm from men with differential levels of sperm DNA fragmentation index (DFI). DESIGN: Prospective study. SETTING: University-affiliated reproductive medicine center. PATIENT(S): A total of 278 male patients consulting for couple infertility were recruited from the First Affiliated Hospital of Wenzhou Medical University. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genome-wide DNA methylation analysis was performed using Infinium MethylationEPIC BeadChip on spermatozoal DNA from 20 male patients. Differentially methylated regions (DMRs) were identified and validated using targeted bisulfite amplicon sequencing in spermatozoal DNA from 266 males. RESULT(S): Unsupervised hierarchical clustering analysis revealed three main clusters corresponding to sperm DFI levels (low, medium, or high). Between-cluster comparisons identified 959 (medium-low), 738 (high-medium), and 937 (high-low) DMRs. Sixty-six DMRs were validated in the 266-sample cohort, of which nine CpG fragments corresponding to nine genes (BLCAP, DIRAS3, FAM50B, GNAS, MEST, TSPAN32, PSMA8, SYCP1, and TEX12) exhibited significantly altered methylation in those with high DFI (≥25%) compared with those with low DFI (<25%). CONCLUSION(S): We identified and validated a distinct DNA methylation signature associated with sperm DNA damage in a large, unselected cohort. These results indicate that sperm DNA damage may affect DNA methylation patterns in human sperm.