Optimization of EWOC principle in BLRM design for phase 1 oncology trials.

Bayesian logistic regression model (BLRM) is widely used to guide dose escalation decisions in phase 1 oncology trials. An important feature of BLRM design is the appealing safety performance due to its escalation with overdose control (EWOC). However, some recent literature indicates that BLRM with EWOC may have a relatively low probability to find the maximum tolerated dose (MTD) compared to some other dose escalation designs. This work discusses this design problem and proposes a practical solution to improve the performance of BLRM design. Specifically, we suggest increasing the EWOC cutoff from routine value 0.25 to a value between 0.3 and 0.4, which will increase the chance of finding the correct MTD with minimal compromise to overdosing risk. Our comparative simulation studies indicate that BLRM with an increased EWOC cutoff has comparable operating characteristics on the correct MTD selection and over-toxicity control as other dose escalation designs (BOIN, mTPI, keyboard, etc.). Moreover, we compare the methodology and operating characteristics of BLRM designs with various decision rules that allow more flexible overdosing control. A case study of dose escalation in a recent phase 1 oncology trial is provided to show how BLRM with optimal EWOC cutoff operates well in practice.

The emerging role of CARM1 in cancer.

Coactivator-associated arginine methyltransferase 1 (CARM1), pivotal for catalyzing arginine methylation of histone and non-histone proteins, plays a crucial role in developing various cancers. CARM1 was initially recognized as a transcriptional coregulator by orchestrating chromatin remodeling, transcription regulation, mRNA splicing and stability. This diverse functionality contributes to the recruitment of transcription factors that foster malignancies. Going beyond its established involvement in transcriptional control, CARM1-mediated methylation influences a spectrum of biological processes, including the cell cycle, metabolism, autophagy, redox homeostasis, and inflammation. By manipulating these physiological functions, CARM1 becomes essential in critical processes such as tumorigenesis, metastasis, and therapeutic resistance. Consequently, it emerges as a viable target for therapeutic intervention and a possible biomarker for medication response in specific cancer types. This review provides a comprehensive exploration of the various physiological functions of CARM1 in the context of cancer. Furthermore, we discuss potential CARM1-targeting pharmaceutical interventions for cancer therapy.

Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment.

Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development.

Enhanced chemoimmunotherapy of breast cancer in mice by apolipoprotein A1-modified doxorubicin liposomes combined with interleukin-21.

Backgroud: Breast cancer is a prevalent malignancy among women, with triple-negative breast cancer (TNBC) comprising approximately 15-20% of all cases, possessing high invasiveness, drug resistance and poor prognosis. Chemotherapy, the main treatment for TNBC, is limited by toxicity and drug resistance. Apolipoprotein A1 modified doxorubicin liposome (ApoA1-lip/Dox) was constructed in our previous study, with promising anti-tumour effect and improved safety been proved. However, during long-term administration, the problem of cumulative toxicity and insufficient tumour inhibition is still inevitable. Interleukin-21 is a small molecule protein secreted by T cells with various immune regulatory functions. IL-21 has significantly curative effects in numerous solid tumours, but it has the disadvantages of low response rate and short half-life. The combination of chemotherapy and immunotherapy has received increasing attention.Purpose: In this study, ApoA1 drug loading system and long-acting IL-21 are innovatively combined for tumour treatment.Methods: We combined ApoA1-lip/Dox and IL-21 for treatment and evaluated their impact on tumor-infiltrating lymphocytes and CD8+ T and NK cell cytotoxicity.Results: Combined administration significantly improved the tumour-infiltrating lymphocytes and enhanced the cytotoxicity of CD8+ T and NK cells. The combination of ApoA1-lip/Dox and IL-21 exhibits significantly enhanced anti-tumour efficacy with lower toxicity of ApoA1-lip/Dox, providing a new strategy for TNBC treatment with enhanced anti-tumour response and reduced toxicity.

A novel prognostic classification integrating lipid metabolism and immune co-related genes in acute myeloid leukemia.

Background: As a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML. Methods: First, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored. Results: Eight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs. Conclusions: This study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

Agrocybe cylindracea fucoglucogalactan induced lysosome-mediated apoptosis of colorectal cancer cell through H3K27ac-regulated cathepsin D.

Inducing lysosomal dysfunction is emerging as a promising means for cancer therapy. Agrocybe cylindracea fucoglucogalactan (ACP) is a bioactive ingredient with anti-tumor activity, while its mechanism remains obscure. Herein, we found that ACP visibly inhibited the proliferation of colorectal cancer cells, and the IC50 value on HCT-116 cells (HT29 cells) was 490 µg/mL (786.4 µg/mL) at 24 h. RNA-seq showed that ACP regulated mitochondria, lysosome and apoptosis-related pathways. Further experiments proved that ACP indeed promoted apoptosis and lysosomal dysfunction of HCT-116 cells. Moreover, ChIP-seq revealed that ACP increased histone-H3-lysine-27 acetylation (H3K27ac) on CTSD (cathepsin D) promoter in HCT-116 cells, thus facilitating the binding of transcription factor EB (TFEB), and resulted in ascension of CTSD expression. Additionally, ACP triggered mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential and increasing pro-apoptotic protein levels. Notably, Pepstatin A (CTSD inhibitor) availably alleviated ACP-induced apoptosis. Taken together, our results indicated that ACP induced lysosome-mitochondria mediated apoptosis via H3K27ac-regulated CTSD in HCT-116 cells. This study indicates that ACP has anti-cancer potential in the treatment of colorectal cancer.

Characterization of the self-targeting Type IV CRISPR interference system in Pseudomonas oleovorans.

Bacterial Type IV CRISPR-Cas systems are thought to rely on multi-subunit ribonucleoprotein complexes to interfere with mobile genetic elements, but the substrate requirements and potential DNA nuclease activities for many systems within this type are uncharacterized. Here we show that the native Pseudomonas oleovorans Type IV-A CRISPR-Cas system targets DNA in a PAM-dependent manner and elicits interference without showing DNA nuclease activity. We found that the first crRNA of P. oleovorans contains a perfect match in the host gene coding for the Type IV pilus biogenesis protein PilN. Deletion of the native Type IV CRISPR array resulted in upregulation of pilN operon transcription in the absence of genome cleavage, indicating that Type IV-A CRISPR-Cas systems can function in host gene regulation. These systems resemble CRISPR interference (CRISPRi) methodology but represent a natural CRISPRi-like system that is found in many Pseudomonas and Klebsiella species and allows for gene silencing using engineered crRNAs.

Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells.

Immunotherapy especially immune checkpoint inhibitors (ICIs) has brought favorable clinical results for numerous cancer patients. However, the efficacy of ICIs in colorectal cancer (CRC) is still unsatisfactory due to the poor median progression-free survival and overall survival. Here, based on the CRC models, we tried to elucidate novel relapse mechanisms during anti-PD-1 therapy. We found that PD-1 blockade elicited a mild antitumor effect in these tumor models with both increased CD8+ T cells and Treg cells. Gene mapping analysis indicated that proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor, transforming growth factor-ß (TGF-ß), and CD36 were unexpectedly upregulated during PD-1 blockade. To investigate the critical role of these proteins especially PCSK9 in tumor growth, anti-PCSK9 antibody in combination with anti-PD-1 antibody was employed to block PCSK9 and PD-1 simultaneously in CRC. Data showed that neutralizing PCSK9 during anti-PD-1 therapy elicited a synergetic antitumor effect with increased CD8+ T-cell infiltration and inflammatory cytokine releases. Moreover, the proportion of Treg cells was significantly reduced by co-inhibiting PCSK9 and PD-1. Overall, inhibiting PCSK9 can further enhance the antitumor effect of anti-PD-1 therapy in CRC, indicating that targeting PCSK9 could be a promising approach to potentiate ICI efficacy.

SrTiO3 /CuNi-Heterostructure-Based Thermopile for Sensitive Human Radiation Detection and Noncontact Human-Machine Interaction.

Noncontact interactive technology provides an intelligent solution to mitigate public health risks from cross-infection in the era of COVID-19. The utilization of human radiation as a stimulus source is conducive to the implementation of low-power, robust noncontact human-machine interaction. However, the low radiation intensity emitted by humans puts forward a high demand for photodetection performance. Here, a SrTiO3-x /CuNi-heterostructure-based thermopile is constructed, which features the combination of high thermoelectric performance and near-unity long-wave infrared absorption, to realize the self-powered detection of human radiation. The response level of this thermopile to human radiation is orders of magnitude higher than those of low-dimensional-materials-based photothermoelectric detectors and even commercial thermopiles. Furthermore, a touchless input device based on the thermopile array is developed, which can recognize hand gestures, numbers, and letters in real-time. This work offers a reliable strategy to integrate the spontaneous human radiation into noncontact human-machine interaction systems.

Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation.

Objective: The offspring of women with gestational diabetes mellitus (GDM) have a high predisposition to developing type 2 diabetes during childhood and adulthood. The aim of the study was to evaluate how GDM exposure in the second half of pregnancy contributes to hepatic glucose intolerance through a mouse model. Methods: By creating a GDM mouse model, we tested glucose and insulin tolerance of offspring by intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and pyruvate tolerance test (PTT). In addition, we checked the expression of genes IGF2/H19, FoxO1, and DNMTs in the mouse liver by RT-qPCR. Pyrosequencing was used to detect the methylation status on IGF2/H19 differentially methylated regions (DMRs). In vitro insulin stimulation experiments were performed to evaluate the effect of different insulin concentrations on HepG2 cells. Moreover, we detect the interaction between FoxO1 and DNMT3A by chromatin immunoprecipitation-quantitative PCR (Chip-qPCR) and knock-down experiments on HepG2 cells. Results: We found that the first generation of GDM offspring (GDM-F1) exhibited impaired glucose tolerance (IGT) and insulin resistance, with males being disproportionately affected. In addition, the expression of imprinted genes IGF2 and H19 was downregulated in the livers of male mice via hypermethylation of IGF2-DMR0 and IGF2-DMR1. Furthermore, increased expression of transcriptional factor FoxO1 was confirmed to regulate DNMT3A expression, which contributed to abnormal methylation of IGF2/H19 DMRs. Notably, different insulin treatments on HepG2 demonstrated those genetic alterations, suggesting that they might be induced by intrauterine hyperinsulinemia. Conclusion: Our results demonstrated that the intrauterine hyperinsulinemia environment has increased hepatic FoxO1 levels and subsequently increased expression of DNMT3A and epigenetic alterations on IGF2/H19 DMRs. These findings provide potential molecular mechanisms responsible for glucose intolerance and insulin resistance in the first male generation of GDM mice.

Titanium as a Possible Modifier of Inflammation Around Dental Implants.

PURPOSE: The exact etiopathogenesis of peri-implant diseases remains unclear. While significant information on molecular markers is available, studies on biomarkers related to possible biocorrosion are sparse. This study aimed to evaluate periimplant crevicular fluid (PICF) for possible titanium (Ti) contamination and explore associations between clinical findings, inflammatory mediators, and Ti levels. MATERIALS AND METHODS: Patients with implant-supported restoration (≥ 1 year in function) were recruited for this cross-sectional study. Demographics, systemic, and periodontal health history were recorded. Clinical evaluations were conducted to reach peri-implant/periodontal diagnoses and grade severity of peri-implant soft tissue inflammation. Crevicular fluid (CF) was collected from both implants and adjacent teeth (PICF, gingival crevicular fluid [GCF]) and analyzed for Ti (inductively coupled plasma mass spectrometry) and inflammatory mediators (V-plex assays). Multiple regression analysis with a linear mixed effect model was used to analyze possible associations between clinical diagnosis, PICF/GCF cytokine, and Ti concentrations. RESULTS: Seventy-seven patients (aged 62 ± 2 years; 39 male) with 117 implants (9 ± 1 years in function) were recruited. Diabetes, positive periodontitis history, and current/former smoking were reported by 8%, 39%, and 39% of subjects, respectively. Seventy-nine implant sites (63 patients) were included in CF cytokine analysis, and 45 of these sites (42 patients) were paired with Ti analysis. Statistically significant increases from health to disease were noted in log-transformed PICF concentrations of IL-1ß, IL-6, IL-10, and INF-γ (P ≤ .05). Also, statistically significant increases from health to severe clinical inflammation were detected in log-transformed PICF concentrations of IL-8, IL-13, and TNF-α (P ≤ .05). Ti was detected in the majority (82%) of PICF and GCF samples. There was no statistically significant difference in log-transformed Ti concentration based on disease status. However, log-transformed Ti concentration was positively correlated to IL-1ß, IL-2, IL-4, IL-8, IL-13, and INF-γ concentrations when data were adjusted for site-specific health (P ≤ .05). CONCLUSION: Ti was detectable in PICF and adjacent GCF, even in health. Specific inflammatory mediator concentrations were increased in peri-implant disease and significantly associated with Ti concentrations, even when data were adjusted for peri-implant health status. Increased GCF inflammatory mediator concentrations were also associated with increased Ti concentrations. Ti effects on peri-implant as well as periodontal tissues require additional longitudinal investigations.

Aesthetic crown lengthening and lip repositioning surgery: Pre- and post-operative assessment of smile attractiveness.

AIM: To assess the effect of aesthetic crown lengthening (ACL) and lip repositioning surgery (LRS) on perception of smile attractiveness. MATERIALS AND METHODS: Preoperative and 6-month postoperative smile photographs of ACL- or LRS-treated patients were evaluated by 100 raters (five gender-balanced groups of ten per procedure) of diverse background (dental students, general dentists, periodontists and laypersons with and without any aesthetic concerns about their own smile). Smile attractiveness was rated by visual analogue scale (VAS). Multivariate mixed-effect models were applied to determine the effect of procedure, rater (age, gender and group) and case (gingival display and GD) on smile attractiveness rating. RESULTS: Average preoperative and postoperative VAS scores for ACL patients were 3.8 ± 2.0 and 6.2 ± 1.9, respectively. Corresponding LRS patient values were 4.8 ± 2.0 and 6.4 ± 1.9. Treatment, baseline GD and rater age were significant determinants (p < .001) of smile attractiveness for both procedures. Rater gender was not significant. Rater group was significant (p < .032) only for ACL. Procedure (p < .001), baseline VAS (p < .001), change in GD (p ≤ .002) and rater age (p ≤ .017) were significant determinants of smile attractiveness change from preoperative to postoperative. CONCLUSIONS: ACL and LRS are two periodontal plastic surgery procedures that deliver significant smile attractiveness improvements, in the eyes of both laypersons and dental professionals.

Lip repositioning surgery for gummy smile: 6-month clinical and radiographic lip dimensional changes.

OBJECTIVES: The present case series aimed to examine lip repositioning surgery (LRS) outcomes related to changes in external and internal upper lip (UL) dimensions, utilizing both conventional clinical and novel radiographic approaches. MATERIALS AND METHODS: Patients (n = 13) diagnosed with hypermobile UL (>8-mm mobility during smile) and excessive gingival display (≥4-mm) were included and assessed at baseline and 6 months postoperatively. Clinical parameters at rest included total lip and internal lip length (vestibular depth). At maximum smile included total lip, philtrum (ergotrid), and vermilion lengths. Cephalometric parameters included anterior maxillary height; lip length; nasolabial angle; anteroposterior lip thickness; internal lip length (vestibular depth); and vestibular fornix position (using novel approach employing radiopaque marker). Linear mixed-effect models, Pearson's correlation, and linear regression were used for statistical analyses. RESULTS: LRS did not affect total UL length at rest (p = 0.418). It resulted in significant internal UL length decrease (-3.8 ± 2.1 mm, p < 0.001) and significant increases of vermilion length (1.9 ± 1.0 mm, p < 0.001) and anteroposterior lip thickness (0.7 ± 0.7 mm, p = 0.002). The clinical and radiographic measurements of total UL length at rest (r ≥ 0.734) and of internal UL length (r ≥ 0.737), and the two radiographic assessments of vestibular depth (r = 0.842), were strongly correlated. CONCLUSIONS: LRS resulted in significant decrease of vestibular depth/internal UL length and in significant increases of UL vertical vermilion length and UL anteroposterior thickness, without affecting total UL length at rest. CLINICAL RELEVANCE: The documented lip dimensional outcomes should help practitioners when treatment-planning LRS and counseling patients seeking treatment for hypermobile UL.

Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses.

Dendritic cell-based cancer vaccines (DC vaccines) have been proved efficient and safe in immunotherapy of various cancers, including melanoma, ovarian and prostate cancer. However, the clinical responses were not always satisfied. Here we proposed a novel strategy to prepare DC vaccines. In the present study, a fusion protein SNU containing a secretin-penetratin (SecPen) peptide, NY-ESO-1 and ubiquitin was designed and expressed. To establish the DC vaccine (DC-SNU), the mouse bone marrow-derived DCs (BMDCs) were isolated, pulsed with SNU and maturated with cytokine cocktail. Then peripheral blood mononuclear cells (PBMCs) from C57BL/6 mice inoculated intraperitoneally with DC-SNU were separated and cocultured with MC38/MC38 NY-ESO-1 tumor cells or DC vaccines. The results show that SNU was successfully expressed. This strategy made NY-ESO-1 entering cytoplasm of BMDCs more efficiently and degraded mainly by proteasome. As we expected, mature BMDCs expressed higher CD40, CD80 and CD86 than immature BMDCs. Thus, the PBMCs released more IFN-γ and TNF-α when stimulated with DC-SNU in vitro again. What's more, the PBMCs induced stronger and specific cytotoxicity towards MC38 NY-ESO-1 tumor cells. Given the above, it demonstrated that DC-SNU loaded with SecPen and ubiquitin-fused NY-ESO-1 could elicit stronger and specific T cell immune responses. This strategy can be used as a platform for DC vaccine preparation and applied to various cancers treatment.

Reversal of Multidrug Resistance by Apolipoprotein A1-Modified Doxorubicin Liposome for Breast Cancer Treatment.

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.

An Ultrasound Model to Predict the Short-Term Effects of Endovascular Stent Placement in the Treatment of Carotid Artery Stenosis.

Purpose: The present study aimed to explore the predictive ability of an ultrasound linear regression equation in patients undergoing endovascular stent placement (ESP) to treat carotid artery stenosis-induced ischemic stroke. Methods: Pearson's correlation coefficient of actual improvement rate (IR) and 10 preoperative ultrasound indices in the carotid arteries of 64 patients who underwent ESP were retrospectively analyzed. A predictive ultrasound model for the fitted IR after ESP was established. Results: Of the 10 preoperative ultrasound indices, peak systolic velocity (PSV) at stenosis was strongly correlated with postoperative actual IR (r = 0.622; P < 0.01). The unstable plaque index (UPI; r = 0.447), peak eccentricity ratio (r = 0.431), and plaque stiffness index (ß; r = 0.512) moderately correlated with actual IR (P < 0.01). Furthermore, the resistance index (r = 0.325) and the dilation coefficient (r = 0.311) weakly correlated with actual IR (P < 0.05). There was no significant correlation between actual IR and the number of unstable plaques, area narrowing, pulsatility index, and compliance coefficient. In combination, morphological, hemodynamic, and physiological ultrasound indices can predict 62.39% of neurological deficits after ESP: fitted IR = 0.9816 - 0.1293ß + 0.0504UPI - 0.1137PSV. Conclusion: Certain carotid ultrasound indices correlate with ESP outcomes. The multi-index predictive model can be used to evaluate the effects of ESP before surgery.

Poseidonibacter antarcticus sp. nov., isolated from Antarctic intertidal sediment.

A Gram-reaction-negative, aerobic, flagellated and coccoid-shaped bacterial strain, designated SM1702T, was isolated from Antarctic intertidal sediment collected off Ardely Island, West Antarctica. The strain grew at 0-30 °C and with 0.5-5.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences and single-copy orthologous clusters both showed that strain SM1702T, together with Poseidonibacter lekithochrous, occupied an independent phylogenetic branch, sharing the highest 16S rRNA gene sequence similarity with type strain of the latter (95.6 %). The major fatty acids were summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), summed feature 8 (C18 : 1 ω7c and/or C18 : 1 ω6c), C16 : 0, and summed feature 2 (C14 : 0 3-OH and/or iso-C16 : 1 I). Polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The genomic DNA G+C content of strain SM1702T was 27.1 mol%. Based on the results of the polyphasic characterisation for strain SM1702T, it is identified as the representative of a novel species of Poseidonibacter, for which the name Poseidonibacter antarcticus sp. nov. is proposed. The type strain of Poseidonibacter antarcticus is SM1702T (=MCCC 1K03471T=KCTC 62796T).

Alpinetin inhibits proliferation and migration of ovarian cancer cells via suppression of STAT3 signaling.

Natural bioactive components are increasingly being applied in cancer research. Alpinetin is a type of natural flavonoid primarily derived from Alpinia katsumadai Hayata, which exhibits anti­bacterial and anti­inflammatory properties. Therefore, it may possess anticancer potential and be employed therapeutically for different diseases. The aim of the present study was to investigate the anticancer effects of alpinetin on the SKOV3 ovarian cancer cell line. The effect of alpinetin treatment on SKOV3 cell proliferation, apoptosis, spheroid and colony formation were measured using Cell Counting kit­8, cell apoptosis, 3D spheroid and colony formation assays, respectively. Analysis of the cell cycle was performed using flow cytometry. Western blot analysis was used to determine the protein expression levels of B­cell lymphoma (Bcl)­2, Bcl­2­associated X protein, cleaved caspase­3, cleaved poly (ADP­ribose) polymerase (PARP), cyclin D1, cyclin­dependent kinase (CDK) 4, CDK6, signal transducer and activator of transcription (STAT) 3, phosphorylated (p)­STAT3, c­myc, survivin, tissue inhibitor of metalloproteinase (TIMP)­1, TIMP­2, matrix metalloproteinase (MMP)­2 and MMP­9. In addition, a wound healing assay was used to determine cancer cell migration. The results revealed alpinetin suppressed cell viability and induced apoptosis of SKOV3 cells in a dose­ and time­dependent manner, and cells were arrested in the G1 phase. Alpinetin treatment upregulated protein expression levels of Bax, cleaved caspase­3 and PARP, and downregulated protein expression levels of Bcl­2, cyclin D1, CDK4 and CDK6. Alpinetin also inhibited cell migration, through increased protein expression levels of TIMP­1 and TIMP­2, and decreased protein expression levels of MMP­2 and MMP­9. Alpinetin also significantly suppressed colony and spheroid formation by SKOV3 cells. In addition, the STAT3 pathway was suppressed as demonstrated by downregulation of p­STAT3 and reduced expression of downstream factors, including c­myc and survivin. Overall, these results indicated that alpinetin may have anticancer effects on human ovarian cancer by inhibiting the STAT3 signaling pathway.

GalNAc-T4 putatively modulates the estrogen regulatory network through FOXA1 glycosylation in human breast cancer cells.

GALNT4 belongs to a family of N-acetylgalactosaminyltransferases, which catalyze the transfer of GalNAc to Serine or Threonine residues in the initial step of mucin-type O-linked protein glycosylation. This glycosylation type is the most complex post-translational modification of proteins, playing important roles during cellular differentiation and in pathological disorders. Most of the breast cancer subtypes are estrogen receptor positive, and hence, the estrogen pathway represents a key regulatory network. We investigated the expression of GalNAc-T4 in a panel of mammary epithelial cell lines and found its expression is associated with the estrogen status of the cells. FOXA1, a key transcription factor, functions to promote estrogen responsive gene expression by acting as a cofactor to estrogen receptor alpha (ERα), but all the aspects of this regulatory mechanism are not fully explored. This study found that knockdown of GALNT4 expression in human breast cancer cells attenuated the protein expression of ERα, FOXA1, and Cyclin D1. Further, our immunoprecipitation assays depicted the possibility of FOXA1 to undergo O-GalNAc modifications with a decrease of GalNAc residues in the GALNT4 knockdown cells and also impairment in the FOXA1-ERα association. Rescuing GALNT4 expression could restore the interaction as well as the glycosylation of FOXA1. Together, these findings suggest a key role for GalNAc-T4 in the estrogen pathway through FOXA1 glycosylation.