Search

Implants with deficient papillae and black triangles are common findings. The treatment of these esthetic complications is considered to be challenging with limited predictability. Therefore, the present report aims to describe a novel technique for papilla augmentation: the "iceberg" connective tissue graft (iCTG) after extraction and interproximal bone reconstruction in the anterior region. A 35-year-old patient presented with a hopeless tooth with interproximal clinical attachment loss extending to the apical third of the adjacent tooth. Interproximal bone reconstruction was performed through alveolar ridge preservation by directly applying recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to the exposed root surface of the adjacent tooth. A mixture of autogenous bone chips (obtained from the ramus) and bovine bone xenograft particles (previously mixed with the growth factor) was also used. The patient was able to return for implant therapy only 2 years later, at which time an incomplete regeneration of the interproximal bone was observed. Therefore, to compensate the interproximal deficiency, the iCTG approach was utilized, involving a double layer of CTG with different origins. Two small grafts from the tuberosity were sutured to the mesial and distal ends of a wider CTG harvested from the palate, aiming to gain additional volume at the interproximal sites. The composite graft was then sutured on top of the implant platform, and the flap was then released and closed by primary intention. After conditioning the peri-implant tissues, the case was finalized with a satisfactory outcome. The described iCTG could be an effective approach for reconstructing peri-implant papillae following interproximal bone reconstruction. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of using a customized xenograft shell with a 1:1 mixture of particulate xenograft and autogenous bone for the reconstruction of horizontally deficient anterior maxillary alveolar ridges. Materials and Methods: CBCT images of the atrophic maxilla of eight patients were acquired and generated into 3D models. The data were transferred to a 3D printer for fabrication. During the surgery, xenograft blocks were manually sliced and customized on the 3D-printed models into bone shells. Then they were fixed to the atrophic site, and the gap was augmented with a 1:1 mixture of particulate xenograft and autogenous bone. Results: Clinical assessment showed no adverse effects; however, one patient exhibited wound dehiscence. The mean difference between the preoperative and 6-month postoperative CBCTs showed a net average bone gain of 4.06 mm at 2 mm from the crest and 4.34 mm at 5 mm from the crest, which was statistically significant. On the other hand, a statistically significant graft resorption of 1.41 mm at 2 mm from the crest and 2.19 mm at 5 mm from the crest was found when the mean difference between the immediate and 6-month postoperative CBCTs was calculated. Conclusions: Within the limitations of the study, the use of xenograft shells as a barrier for maxillary alveolar ridge reconstruction is a predictable technique; however, further investigations regarding the required time for graft consolidation are required. [ABSTRACT FROM AUTHOR]

Purpose: The structural and compositional similarities between dentin and alveolar bone form the basis for utilizing dentin for bone regeneration. Various authors have recommended using treated mineralized, partially demineralized, or demineralized dentin grafts instead of xenografts because of their comparable clinical and radiographic results and lower costs. The current study therefore compared the effect of untreated mineralized dentin grafts (UMDGs) versus xenografts in vertical and horizontal augmentation around dental implants that were immediately placed in the mandibular anterior region. Materials and Methods: A total of 56 patients who required immediate dental implant placement in the mandibular anterior region were randomly allocated to group I (study), where ground dentin was washed with normal saline and placed around the dental implants, or group II (control), where a xenograft was used. The primary implant stability was measured at the time of implant placement. Secondary implant stability, plaque index (PI), bleeding index (BI), probing depth (PD), and keratinized mucosa width (KMW) were assessed at baseline (time of definitive abutment and provisional crown placement) and then at 3, 6, and 12 months. Pain and the number of analgesics consumed were assessed daily during the first postoperative week. Marginal bone loss (MBL) and radiodensity were assessed radiographically. Results: There were no significant differences between the groups in terms of postoperative pain, the number of analgesic tablets consumed, peri-implant mucositis, or peri-implantitis. Both groups showed comparable results for the PI, BI, and PD. Moreover, there was no statistical difference between the groups with regard to primary implant stability and secondary implant stability at baseline and 12 months. Group I showed significantly lower secondary implant stability after loading at 3 and 6 months and significantly greater bone loss and lower bone density before exposure. KMW and MBL after exposure were significantly higher in group I at all time points. Conclusions: Although UMDGs showed similar clinical results to xenografts, including primary and secondary implant stability, they had higher resorption rates than xenografts. Therefore, treatment of the dentin graft is required. Thus, the authors do not recommend using UMDGs. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to compare the histomorphometrically evaluated new bone formation (NB), the radiographically measured graft stability, and the clinical implant outcome for maxillary sinus augmentation grafted with deproteinized bovine bone mineral (DBBM) with either small (Bio-Oss-S, Geistlich) or large (Bio-Oss-L, Geistlich) particles. Materials and Methods: Using a split-mouth study design, bilateral maxillary sinus augmentation was performed in 13 patients either with Bio-Oss-S particles (0.25 to 1 mm) or Bio-Oss-L particles (1 to 2 mm). After a healing period of 6 months, bone biopsies were axially retrieved in the molar region for histologic/histomorphometric analysis of NB, including subsequent staged implant placement. To determine graft stability, the maxillary sinus augmentation vertical graft heights were radiographically measured immediately after sinus augmentation, at implant placement, and at the 2- and 4-year post-augmentation follow-ups. In addition, the clinical implant-prosthodontic outcome (survival/success/marginal bone loss) was assessed at 1 and 3 years post-loading. Results: A total of 22 sinuses from 11 patients with split-mouth evaluation were ultimately available for data and statistical analysis. Histomorphometric analysis of the axially retrieved bone biopsies revealed the presence of NB (S: 25.5% ± 7.0% vs L: 23.6% ± 11.9%; P = .640), residual graft particles (S: 19.6% ± 9.2% vs L: 17.5% ± 6.3%; P = .365) as well as connective tissue (S: 54.9% ± 9.2% vs L: 58.9% ± 12.5%; P = .283), without significant differences between the use of small (Bio-Oss-S) and large (Bio-Oss-L) particles. However, there was significantly (P = .021) higher bone-to-graft contact (BGC) for the small-particle graft sites (27.9% ± 14.8%) compared to the large-particle graft sites (19.9% ± 12.9%), representing a significantly higher osteoconductivity. Both particle sizes showed significant (P < .01) vertical graft height reduction over time (4 years) of about 10%, with predominant graft reduction in the time period between sinus augmentation and implant placement compared to any follow-up periods after implant placement. At the 3-year post-loading implant evaluation, all implants and prostheses survived (100%), and the peri-implant marginal bone loss (S: 0.52 ± 0.19 mm; L: 0.48 ± 0.15 mm) as well as the peri-implant health conditions (S: 87.5%, L:81.2%) did not differ between implants inserted with the two different xenograft particles used. Conclusions: The use of small and large bovine xenograft particles for maxillary sinus augmentation provides for comparable bone formation, ensuring stable graft dimensions combined with high implant success and healthy peri-implant conditions. However, small particle size resulted in a higher BGC, providing for higher osteoconductivity than with the larger particle size. [ABSTRACT FROM AUTHOR]

Objectives: This case series aimed to assess the efficacy of a novel horizontal ridge augmentation modality using histology. Combinations of "sticky bone" and tenting screws without autologous bone were used as augmentative materials. Method and materials: Five individuals presenting healed, atrophic, partially edentulous sites that required horizontal bone augmentation before implant placement were enrolled. Patients underwent the same augmentation type and 5 months of postoperative reentry procedures. The first surgery served as implant site development, whereas the biopsy and corresponding implant placement were performed during reentry. The bone was qualitatively analyzed using histology and histomorphometry and quantitatively evaluated using CBCT. Results: Four individuals healed uneventfully. Early wound dehiscence occurred in one case. Histology showed favorable bone substitute incorporation into the newly formed bone and intimate contact between de novo bone and graft material in most cases. Histomorphometry revealed an average of 48 ± 28% newly formed bone, 19 ± 13% graft material, and 33 ± 26% soft tissue components. The CBCTbased mean alveolar ridge horizontal increase was 3.9 ± 0.6 mm at 5 months postoperatively. Conclusions: The described augmentation method appears suitable for implant site development resulting in favorable bone quality according to histology. However, clinicians must accommodate 1 to 2 mm of resorption in augmentative material width at the buccal aspect. [ABSTRACT FROM AUTHOR]

Objective: Mucogingival surgery involving tissue grafts is commonly employed for cosmetic procedures like root coverage, and is increasingly applied in implant therapy to modulate peri-implant soft tissues and enhance implant survival. These procedures involve harvesting autologous connective or epithelial connective tissue, often from the palate or tuber maxillae. However, this can cause patient morbidity due to postoperative pain. Substitute materials, including animal-derived and xenografts, have been developed but lack qualities of autologous grafts. Method and materials: To address postoperative discomfort, a novel technique, named "palatal shield," using composite resin stabilized on adjacent teeth's palatal surface is proposed as an aid to donor site healing after mucogingival procedures. Two cases are reported where this technique was successfully applied. The first case involves a 53-year-old woman undergoing free gingival graft surgery for peri-implant treatment. The second case features a 58-year-old man receiving subepithelial connective tissue graft surgery for root sensitivity. Results: Ten days post surgery, both patients reported excellent postoperative comfort. The technique's effectiveness is highlighted in these cases, demonstrating its applicability in various surgical cases involving free gingival graft or connective tissue graft harvesting. Conclusion: The proposed "palatal shield" technique offers several advantages, including enhanced patient comfort, ease of application, and cost-effectiveness, making it a promising addition to mucogingival surgical procedures. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present study was to evaluate clinical and radiographic outcomes of implants placed in alveolar sockets treated by means of alveolar ridge preservation after 10 years of follow-up. Method and materials: Eleven patients treated with 11 implants placed after alveolar ridge preservation using bovine-derived xenograft particles and collagen membrane were selected. Full-mouth plaque score, full-mouth bleeding score, probing depth at four sites per implant, and radiographic marginal bone level at mesial and distal aspects for each implant were recorded at baseline and after 10 years of follow-up. The primary outcome was the radiographic marginal bone loss. The marginal bone loss was considered as the difference between marginal bone level at baseline and after 10 years of observation time. Results: After 10 years of follow-up, full-mouth plaque score increased significantly (P < .05), while no statistically significant differences were found in the change in full-mouth bleeding score (P = .05). At the 10-year observation period, a significant increase in probing depth was observed at all sites (P < .05), except at the mesial aspects (P = .05). Radiographic marginal bone loss was 1.1 ± 0.1 mm and 1.0 ± 0.1 mm at mesial and distal sites, respectively. Conclusion: Whitin the limitations of the present study, implants placed in post-extraction sockets treated with alveolar ridge preservation yielded stable clinical and radiographic results after 10 years of follow-up. [ABSTRACT FROM AUTHOR]

This randomized controlled trial aimed to determine the clinical efficacy of xenogeneic collagen membrane (XCM) derived from porcine peritoneum in combination with a coronally advanced flap (CAF) in the management of gingival recession defects and to compare the outcomes to those of connective tissue grafts (CTGs). A total of 12 systemically healthy individuals presenting with 30 isolated/multiple Cairo RT 1/2 gingival recession defects in maxillary canines and premolars were randomly treated either with CAF + XCM or CAF + CTG. Recession height (RH), gingival biotype (GB), gingival thickness (GT), width of keratinized gingiva (WKG), and width of attached gingiva (WAG) were recorded at baseline and at 3, 6, and 12 months. Patient perceptions of pain and esthetics and the modified root coverage esthetic score (MRES) were also documented. From baseline to 12 months, both groups showed a significant reduction in mean RH (CAF + CTG: 2.73 ± 0.79 mm to 0.33 ± 0.61 mm; CAF + XCM: 2.73 ± 0.88 mm to 1.20 ± 0.77 mm). At 12 months, CAF + CTG sites had a mean root coverage percentage (MRC%) of 85.60% ± 28.74%, whereas CAF + XCM sites had an MRC% of 55.13% ± 31.22%. CAF + CTG-treated sites had significantly better outcomes, with a greater number of sites achieving complete root coverage (n = 11) and higher MRES scores than the porcine peritoneal membrane group (P < .05). [ABSTRACT FROM AUTHOR]

Purpose: To investigate bone regeneration among three different bone graft materials in a rat calvarum model. Materials and Methods: A total of 24 rats had two 5-mm defects placed per calvarial. Rats were divided into four groups: bovine xenograft (XG), demineralized bone matrix (DBM), mineralized bone graft (MBG), and collagen membrane control (CC). Within each group, samples were collected at two time points: 4 weeks (T4) and 8 weeks (T8). Bone regeneration was assessed by microcomputed tomography (micro-CT) imaging and was analyzed using MATLAB software. Additionally, the fixed samples were subsequently demineralized for immunohistochemistry and histomorphometry. Slides were mounted and stained with hematoxylin and eosin (H&E) stain as well as bone morphogenetic protein 2 (BMP-2) and runt-related transcription factor 2 (RUNX2) markers. The numbers of positive cells/area were calculated for each group and analyzed. Results: At 4 weeks, DBM showed low mineral density (7.7%) compared to the control (25.2%), but increased dramatically at 8 weeks (DBM, T8 = 27.6%; CC, T8 = 27.2%). Xenograft material showed an increase in mineral desnity between T4 and T8 (XG, T4 = 25.0%; XG, T8 = 32.3%). MBG remained consistent over the 8-week trial period (MBG, T4 = 30.4%; MBG, T8 = 30.4%). BMP-2 expression was present in cells adherent to all graft materials. RUNX2 expression was also observed in cells adherent to all graft materials, indicating that during the 4- to 8-week healing period, all materials supported osteogenesis. Conclusions: Compared to other materials, the DBM had high osteoinductive properties during the 4- to 8-week time period based on increased mineral content. All materials were associated with immunohistologic evidence of osteogenesis in the rat calvarial defect model. [ABSTRACT FROM AUTHOR]

Xenogeneic-derived biomaterials are among the most routinely employed bone substitutes for immediate grafting of extraction sites as a modality of alveolar ridge preservation (ARP). The deproteinized bovine bone material is widely used and documented around the world. The present pilot clinical trial evaluated and compared the clinical and morphologic alterations of extraction sites after ARP using two commercially available yet differently processed bovine bone grafts. A total of 20 adjacent extraction sites in 10 patients were included. All sites received the exact same ARP therapy except for the type of bovine bone graft, which was randomly assigned between two adjacent extraction sockets in 10 patients (Group A received Bio-Oss particles and Group B received Cerabone particles). At all sites, healing was monitored at the time of surgery and at 1, 2, 3, and 4 months postoperative. All of the augmented extraction sites achieved successful implant therapy regardless of the bone graft material used for ARP. Six weeks after implant placement, second-stage/uncovering procedures were performed without complications. Intergroup comparisons of the crestal gingival healing process (CGHP), mean transversal crestal ridge resorption (MTRR), and mean implant primary stability (MIPS) were in favor of Group A sites (treatment with Bio-Oss particles). [ABSTRACT FROM AUTHOR]

Purpose: To compare bone substitutes composed of glycated collagen with synthetic micro-sized (1 to 10 µm) hydroxyapatite (OB) vs non-cross-linked collagen matrix with large-particle (250 to 1,000 µm) bovine-derived hydroxyapatite (BOC). Materials and Methods: The P1 to P4 premolars were bilaterally extracted from the mandibles of 19 Beagle dogs. After 21 days, osteotomies were created in each dog that received OB or BOC and were covered with a collagen membrane or were left untreated. The animals were randomly divided into three groups based on sacrifice time (4, 12, or 24 weeks). The right and left hemimandibles were trimmed to facilitate imaging and histology, and all tissues were placed in 10% neutral-buffered formalin. Microcomputed tomography (MicroCT 40 Scanner, Scanco) was used to analyze bone sections. Bone volume, residual material volume, and bone mineral density were determined for each treatment site (OB and BOC) based on a volume of interest that encompassed the original defect. Additionally, blinded histopathologic assessment (based on the ISO 10993-6 scoring system) and histomorphometry were performed on sections ground to < 100 µm thick and stained with Stevenel's blue. Results: No clinical side effects were noted. No statistical differences were observed for OB vs BOC regarding the mineral volume percentage. Compared to OB, BOC had significantly higher mean mineralization densities at 12 weeks (P < .01), but this difference did not extend to 24 weeks. For residual grafting material, bone maturation, alveolar ridge restoration, and inflammatory response, OB showed a residual amount of bone graft and no statistical differences compared to BOC. Conclusion: Both OB and BOC represent valid treatment options for critically sized bone defects. Both bone fillers outperformed the sham-operated, ungrafted (empty) control, demonstrating statistically improved bone growth and ridge restoration. [ABSTRACT FROM AUTHOR]

Objectives: Low bone density and lack of adequate vertical bone dimension as a result of maxillary sinus pneumatization present some of the most problematic cases for endosseous implant applications in posterior maxillary regions that hinder prosthetic rehabilitation. The overall objectives of the study were to assess the histologic, histomorphometric, and radiologic evaluation of biopsies gathered from maxillary sinuses that were grafted with three different bovine bone particles (Bio-Oss, Cerabone, and Ti-Oss) and analyze the volume of the bone graft and the quantity of new bone formation. Method and materials: Thirty-six patients with < 4 mm of residual ridge height unilaterally in the posterior maxilla were equally divided into three groups, each of which received different bovine bone particles for maxillary sinus augmentation. Six months later, biopsies were harvested for histologic and histomorphometric evaluations. Volumetric changes in maxillary sinus augmentation were analyzed at 1-week and 6-month time-points following maxillary sinus augmentation surgery. Results: Histomorphometric and histologic analysis revealed a significant difference between the Ti-Oss group compared with the Bio-Oss and Cerabone groups (P=.011). In terms of residual graft particlesand soft tissue, there were no significant differences between groups. 3D volumetric reductions between 1-week (baseline) and 6-month time-points recorded significant graft volume reduction in all groups (P < .05). Significantly greater bone resorption and lower new-bone formation were manifested in the Ti-Oss group in comparison to the other groups. Conclusions: Within the limits of thisstudy, histologic and radiologic results indicated that Bio-Oss and Cerabone could be used efficiently in sinus augmentation procedures, while further prospective studies are needed to evaluate the Ti-Oss material in maxillary sinus augmentation. [ABSTRACT FROM AUTHOR]

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114–amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor–bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma. Editor's summary: Upstream open reading frames (uORFs) are RNA sequences encoding short peptides that mainly function as translational represssors. Here, Li et al. show that the uORF of the oncogene MYC is translated into a peptide (MPEP) that is secreted from glioblastoma stem cells (GSCs). MPEP expression promoted proliferation of GSCs in vitro and accelerated tumorigenesis in a mouse model. MPEP acted through canonical activation of tropomyosin receptor kinase B, which was corroborated by the increase in survival rates of glioblastoma mice undergoing combination treatment with an MPEP antibody and the TRK inhibitor entrecitinib. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer is a challenging disease to treat, and new therapies are needed to improve patient outcomes. Okanin, a natural compound derived from Bidens pilosa L., has been known for its anti-inflammatory properties, but its effects on cancer, particularly oral cancer, are less understood. In this study, we investigated the anticancer potential of okanin in human oral cancer cells. Our results showed that okanin effectively reduced the growth of oral cancer cells by inducing cell death through mechanisms involving both apoptosis and pyroptosis. Additionally, okanin inhibited tumor growth in a mouse model of oral cancer. These findings suggest that okanin may be a promising natural compound for developing new treatments for oral cancer. Background: Okanin, a flavonoid compound derived from Bidens pilosa L., has garnered attention for its anti-inflammatory properties. Although Bidens pilosa is commonly used in healthcare products and functional foods, the anticancer potential of okanin, particularly in oral cancer, remains underexplored. This study aims to investigate the effects of okanin on oral cancer cell lines and its potential as a therapeutic agent. Methods: The study involved assessing the cytotoxic effects of okanin on oral cancer cell lines SAS, SCC25, HSC3, and OEC-M1. The IC50 values were determined using methylene blue assays, and the clonogenic capacity was evaluated through colony formation assays. Flow cytometry was used to analyze cell cycle progression and apoptosis. Caspase-3/7 activity assays and annexin V/7-AAD staining confirmed the induction of apoptosis and pyroptosis. In vivo efficacy was assessed using a SAS xenograft model, and immunohistochemical analysis of xenograft tissue was performed to examine pyroptosis-related markers. Results: Okanin exhibited potent cytotoxic effects with IC50 values of 12.0 ± 0.8, 58.9 ± 18.7, 18.1 ± 5.3, and 43.2 ± 6.2 μM in SAS, SCC25, HSC3, and OEC-M1 cells, respectively. It caused dose- and time-dependent reductions in cell viability and significantly impaired clonogenic capacity. Flow cytometry revealed G2/M cell cycle arrest and increased sub-G1 population, indicating cell cycle disruption and death. Okanin induced both apoptosis and pyroptosis, as confirmed by caspase-3/7 activity and annexin V/7-AAD staining. In vivo, okanin reduced tumor growth and involved pyroptosis-related markers such as CASP1, GSDMC, GSDMD, and GSDME. Conclusions: Okanin demonstrates significant anticancer potential, particularly in oral cancer, by inducing both apoptosis and pyroptosis. Its efficacy in reducing tumor growth in vivo further supports its potential as a novel therapeutic option. Further mechanistic studies are needed to elucidate the pathways involved in okanin-mediated cell death and to explore its clinical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer (NSCLC) accounts for 80–85% of primary lung cancers. Radiation therapy is widely used to treat both primary NSCLC and lung cancer that has spread to the brain. However, radiotherapy responses are not durable and toxicity limits therapy. Therefore, there is an urgent need for new agents that can enhance the effectiveness of radiation therapy in lung cancer and reduce its toxicity. We find that AM-101, a benzodiazepine analog, enhances the effects of radiation and significantly improves the survival of mice with lung cancer brain-metastatic tumors. Additionally, AM-101 makes radiation treatment work better and slows down the growth of NSCLC subcutaneous xenograft tumors in mice. AM-101 activates the GABA(A) receptor in lung cancer cells, triggering selective autophagy by causing GABARAP to form multimers and stabilizing the mitochondrial receptor Nix. GABA(A) receptor activation may improve tumor control and allow for lower radiation doses, reducing toxicity. In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. [ABSTRACT FROM AUTHOR]

Background: Ameloblastoma and odontogenic keratocyst (OKC) are odontogenic tumors that develop from remnants of odontogenic epithelium. Both display locally invasive growth characteristics and high predilection for recurrence after surgical removal. Most ameloblastomas harbor BRAFV600E mutation while OKCs are associated with PATCH1 gene mutation but distinctive indicators of ameloblastoma growth characteristics relative to OKC are still unclear. The aim of this study was to assess hub genes that underlie ameloblastoma growth characteristics using bioinformatic analysis, ameloblastoma samples and mouse xenografts of human epithelial-derived ameloblastoma cells. Methods: RNA expression profiles were extracted from GSE186489 gene expression dataset acquired from Gene Expression Ominibus (GEO) database. Galaxy and iDEP online analysis tools were used to identify differentially expressed genes that were further characterized by gene ontology (GO) and pathway analysis using ShineyGO. The protein-protein interaction (PPI) network was constructed for significantly upregulated differentially expressed genes using online database STRING. The PPI network visualization was performed using Cytoscape and hub gene identification with cytoHubba. Top ten nodes were selected using maximum neighborhood component, degree and closeness algorithms and analysis of overlap was performed to confirm the hub genes. Epithelial-derived ameloblastoma cells from conventional ameloblastoma were transplanted into immunocompromised mice to recreate ameloblastoma in vivo based on the mouse xenograft model. The top 3 hub genes FN1, COL I and IGF-1 were validated by immunostaining and quantitative analysis of staining intensities to ameloblastoma, OKC samples and mouse ameloblastoma xenografts tissues. Results: Seven hub genes were identified among which FN1, COL1A1/COL1A2 and IGF-1 are associated with extracellular matrix organization, collagen binding, cell adhesion and cell surface interaction. These were further validated by positive immunoreactivity within the stroma of ameloblastoma samples but both ameloblastoma xenograft and OKC displayed only FN1 and IGF-1 immunoreactivity while COL 1 was unreactive. The expression levels of both FN1 and IGF-1 were much lower in OKC relative to ameloblastoma. Conclusion: This study further validates a differentially upregulated expression of matrix proteins FN1, COL I and IGF-1 in ameloblastoma relative to OKC. It suggests that differential stromal architecture and growth characteristics of ameloblastoma relative to OKC could be an interplay of differentially upregulated genes in ameloblastoma. [ABSTRACT FROM AUTHOR]

Objective: While most xenograft wound matrices are flat sheets not designed for deep or tunnelling wounds, three-dimensional acellular collagen matrices (3D-ACM) can fill deep wound beds and enable full wound wall apposition. This case series examines the use of 3D-ACM in treating diabetic foot ulcers (DFUs) that are deep, tunnelling, undermining, or irregularly shaped. We report outcomes of cases where 3D-ACM was applied to deep or tunnelling DFUs present for at least four weeks. Method: In this retrospective case series, 3D-ACM was applied, healing was monitored and measurements were collected. Additional 3D-ACM was applied as needed. Results: In total, 11 patients with 13 wounds were treated. Improved wound appearance and reduced size were observed at most follow-ups. Mean initial wound depth was 1.6cm, and several wounds showed significant depth reductions shortly after therapy initiation. In total, 62% of wounds (8/13) reached 50% closure by four weeks. Additionally, 54% (7/13) were fully closed by 12 weeks. The remaining 46% (6/13) took between 12–22.3 weeks to heal. Overall mean therapy time was 13.1 weeks (range: 2.0–22.3 weeks). Deeper wounds generally took longer to close. Conclusion: The findings of this case series showed that 3D-ACM could offer a protective microenvironment for wound management for deep or tunnelling DFUs. While some took >12 weeks to close, this may be attributable to large initial depths and volumes, rather than a failure to respond to the treatment modality. Other wounds that require a conforming 3D matrix, enabling full wound wall apposition, may benefit from 3D-ACM. Further investigations would be beneficial to understand the capabilities of this treatment modality. [ABSTRACT FROM AUTHOR]

The objective of this study is to demonstrate the safety and reproducibility of our surgical technique for implanting decellularized vascular xenografts in the carotid artery of sheep. Acellular porcine carotid arteries were implanted as interposition xenografts in seven sheep. An intravascular shunt was used for cerebral protection, and a flowmeter was utilized to assess graft performance. There were no intraoperative deaths or postoperative neurological complications observed. Acute graft thrombosis occurred in one sheep during surgery, but was successfully managed with thrombectomy to restore blood flow. Post-implantation flowmetry and Doppler ultrasound confirmed graft functionality. Our study demonstrates the successful application of our surgical method for implanting decellularized vascular xenografts in the carotid artery of sheep. The implanted grafts maintained patency, normal blood flow, and favorable wound healing and neurological outcomes post-surgery. [ABSTRACT FROM AUTHOR]

This article presents a deep-learning model that uses RNA-seq data to predict the chemoresistance of platinum-based therapy in high-grade serous ovarian carcinoma (HGSOC). The model, which was developed using diverse transcriptome datasets and deep ensemble learning techniques, achieved high performance in predicting chemo-resistant HGSOC patients. The study highlights the importance of accurate prediction methods to guide treatment decisions and improve patient outcomes in HGSOC, a disease with high mortality rates worldwide. The identified genes and prediction models have potential biological relevance and may be useful for further research and application in other ovarian cancer studies with limited sample sizes. [Extracted from the article]

Background/Objectives: Near-infrared photoimmunotherapy (NIR-PIT) was recently approved for the treatment of unresectable locally advanced or recurrent head and neck cancers in Japan; however, only one clinical dose has been validated in clinical trials, potentially resulting in excessive or insufficient dosing. Moreover, IRDye700X (IR700) fluorescence intensity plateaus during treatment, indicating a particular threshold for the antitumor effects. Therefore, we investigated the NIR laser dose across varying tumor sizes and irradiation methods until the antitumor effects of the fluorescence decay rate plateaued. Methods: Mice were subcutaneously transplanted with A431 xenografts and categorized into control, clinical dose (cylindrical irradiation at 100 J/cm², frontal irradiation at 50 J/cm²), and evaluation groups. The rate of tumor IR700 fluorescence intensity decay to reach predefined rates (−0.05%/s or −0.2%/s) until the cessation of light irradiation was calculated using a real-time fluorescence imaging system. Results: The evaluation group exhibited antitumor effects comparable to those of the clinical dose group at a low irradiation dose. Similar results were observed across tumor sizes and irradiation methods. Conclusions: In conclusion, the optimal antitumor effect of NIR-PIT is achieved when the fluorescence decay rate reaches a plateau, indicating the potential to determine the appropriate dose for PIT using a real-time fluorescence monitoring system. [ABSTRACT FROM AUTHOR]

Ral-binding/interacting protein (RLIP) acts as a transporter that responds to stress and provides protection, specifically against glutathione–electrophile conjugates and xenobiotic toxins. Its increased presence in malignant cells, especially in cancer, emphasizes its crucial antiapoptotic function. This is achieved by selectively regulating the cellular levels of proapoptotic oxidized lipid byproducts. Suppressing the progression of tumors in human xenografts can be achieved by effectively inhibiting RLIP, a transporter in the mercapturic acid pathway, without involving chemotherapy. Utilizing ovarian cancer (OC) cell lines (MDAH2774, OVCAR4, and OVCAR8), we observed that agents targeting RLIP, such as RLIP antisense and RLIP antibodies, not only substantially impeded the viability of OC cells but also remarkably increased their sensitivity to carboplatin. To delve further into the cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin, we conducted investigations in both cell culture and xenografts of OC cells. The outcomes revealed that RLIP depletion via phosphorothioate antisense led to rapid and sustained remissions in established subcutaneous human ovary xenografts. Furthermore, RLIP inhibition by RLIP antibodies exhibited comparable efficacy to antisense and enhanced the effectiveness of carboplatin in MDAH2774 OC xenografts. These investigations underscore RLIP as a central carrier crucial for supporting the survival of cancer cells, positioning it as a suitable focus for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Acquired multidrug resistance is often blamed for the failure of chemotherapy in patients with malignant tumors, including chronic myeloid leukemia (CML). In this study, the authors investigated the role of circular RNA 0080145 (circ_0080145) in imatinib (IM) resistance of CML. Materials and Methods: Quantitative real-time polymerase chain reaction was applied to measure the expression of circ_0080145, microRNA-326 (miR-326), and PTPRF interacting protein alpha 1 (PPFIA1) mRNA. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the half maximal inhibitory concentration (IC50) of IM and cell proliferation. Flow cytometry analysis was utilized to assess cell apoptosis. The levels of glucose uptake and lactate production were examined using specific kits. Protein levels were detected through Western blot assay. The targeting relationship between miR-326 and circ_0080145 or PPFIA1 was verified by dual-luciferase reporter assay. The murine xenograft model was constructed to investigate the effect of circ_0080145 in vivo. Results: circ_0080145 was upregulated in IM-resistant CML patients and cells. circ_0080145 silencing suppressed IM resistance, cell growth, and glycolysis and induced apoptosis in IM-resistant CML cells in vitro. Moreover, circ_0080145 knockdown blocked tumor growth and IM resistance in vivo. miR-326 was a target of circ_0080145, and miR-326 inhibition restored the effects of circ_0080145 silencing on cell progression and IM resistance. In addition, PPFIA1 was a target gene of miR-326. The suppressive roles in IM resistance, cell growth and glycolysis, and the promotional role in apoptosis mediated by miR-326 were abolished by PPFIA1 overexpression in IM-resistant CML cells. Conclusion: circ_0080145 contributes to IM resistance via modulating miR-326/PPFIA1 axis, which might provide a novel avenue for CML therapy. [ABSTRACT FROM AUTHOR]

SYT13 is one of the atypical members of the synaptotagmin (SYT) family whose function has attracted considerable attention in recent years. Although SYT13 has been studied in several types of human cancers, such as lung cancer, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. It was demonstrated that SYT13 is significantly upregulated in ESCC tissues compared with normal ones and correlated with higher degree of malignancy. Knockdown of SYT13 could inhibit ESCC cell proliferation and migration, while promoting cell apoptosis. Meanwhile, ESCC cells with relatively lower SYT13 expression grew slower in vivo and finally formed smaller xenografts. Furthermore, acrosomal vesicular protein 1 was identified as a potential downstream target of SYT13, which regulates cell phenotypes of ESCC cells in cooperation with SYT13. All the in vitro and in vivo results in this study identified that SYT13 silencing could be an effective strategy to inhibit the development of ESCC, which could be considered as a promising therapeutic target in the treatment of ESCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Liposarcoma is a rare cancer of adipose tissue with limited treatment options. Here, we studied the fuel used by liposarcoma to develop a new strategy for treatment. Liposarcoma was found to rely on the amino acid Asparagine for tumor growth, especially in its most aggressive form. By combining treatments that limit both synthesis and uptake of Asparagine within liposarcoma cells, we demonstrated a unique sensitivity that reduced tumor growth in animal models. Altogether, findings from this study suggest that targeting Asparagine could be a promising new therapy in liposarcoma. Background: mTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS). Methods: Human tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling. Results: Asn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth. Conclusions: Asn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells exhibit several key characteristics, including uncontrolled growth, altered metabolism, enhanced survival mechanisms, and resistance to apoptosis, all of which are crucial for their persistence. In our study, we explored the impact of disrupting the production of mitochondrial gatekeeper protein VDAC1 on lung cancer. We induced lung cancer in mice using the chemical urethane, which closely mimics human lung cancer in terms of genetic mutations and molecular changes. Using MRI to monitor the lung tumors, we found that inhibiting VDAC1 expression in this mouse model led to significant changes: reprogramming of cancer cell metabolism, reduced tumor growth, alterations in the tumor microenvironment, and elimination of cancer stem cells (CSCs). Additionally, treatment with a peptide derived from VDAC1 also inhibited tumor growth and decreased CSC markers. These findings suggest that targeting VDAC1, either through depletion or with a cell-penetrating peptide, could be a promising therapeutic approach for lung cancer. Alterations in cellular metabolism are vital for cancer cell growth and motility. Here, we focused on metabolic reprogramming and changes in tumor hallmarks in lung cancer by silencing the expression of the mitochondrial gatekeeper VDAC1. To better mimic the clinical situation of lung cancer, we induced lung cancer in A/J mice using the carcinogen urethane and examined the effectiveness of si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles. si-m/hVDAC1-B, given intravenously, induced metabolism reprogramming and inhibited tumor growth as monitored using MRI. Mice treated with non-targeted (NT) PLGA-PEI-si-NT showed many large size tumors in the lungs, while in PLGA-PEI-si-m/hVDAC-B-treated mice, lung tumor number and area were markedly decreased. Immunofluorescence staining showed decreased expression of VDAC1 and metabolism-related proteins and altered expression of cancer stem cell markers. Morphological analysis showed two types of tumors differing in their morphology; cell size and organization within the tumor. Based on specific markers, the two tumor types were identified as small cell (SCLC) and non-small cell (NSCLC) lung cancer. These two types of tumors were found only in control tumors, suggesting that PLGA-PEI-si-m/hVDAC1-B also targeted SCLC. Indeed, using a xenograft mouse model of human-derived SCLC H69 cells, si-m/hVDAC1-B inhibited tumor growth and reduced the expression of VDAC1 and energy- and metabolism-related enzymes, and of cancer stem cells in the established xenograft. Additionally, intravenous treatment of urethane-induced lung cancer mice with the VDAC1-based peptide, Retro-Tf-D-LP4, showed inhibition of tumor growth, and decreased expression levels of metabolism- and cancer stem cells-related proteins. Thus, silencing VDAC1 targeting both NSCLC and SCLC points to si-VDAC1 as a possible therapeutic tool to treat these lung cancer types. This is important as target NSCLC tumors undergo transformation to SCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: The naturally occurring derivative of estrogen, 2-methoxyestradiol (2-ME), has been shown to have good anti-cancer properties. However, it is broken down too quickly within the blood to be clinically useful. We designed 2-ME analogs with modifications which could avoid rapid metabolism, would preferably stay in the tumor, and were more toxic to cancer cells. Here, we looked more closely at how these compounds work within cancer cells, and how they communicate within themselves and with their environment. ESE-15-one and ESE-16 interfere with the functioning of the intracellular cytoskeleton (actin and microtubules), sending messages that stop cell division, intracellular transport of proteins, and cell migration and invasion, eventually inducing cell suicide. They also inhibited the movement of cells that make blood vessels that would support tumor growth. Using eggs with chicken embryos, we could show that the compounds reduced the tumor size and diminished the spread of cancer cells in a living system. The microtubule-disrupting agent 2-methoxyestradiol (2-ME) displays anti-tumor and anti-angiogenic properties, but its clinical development is halted due to poor pharmacokinetics. We therefore designed two 2-ME analogs in silico—an ESE-15-one and an ESE-16 one—with improved pharmacological properties. We investigated the effects of these compounds on the cytoskeleton in vitro, and their anti-angiogenic and anti-metastatic properties in ovo. Time-lapse fluorescent microscopy revealed that sub-lethal doses of the compounds disrupted microtubule dynamics. Phalloidin fluorescent staining of treated cervical (HeLa), metastatic breast (MDA-MB-231) cancer, and human umbilical vein endothelial cells (HUVECs) displayed thickened, stabilized actin stress fibers after 2 h, which rearranged into a peripheral radial pattern by 24 h. Cofilin phosphorylation and phosphorylated ezrin/radixin/moesin complexes appeared to regulate this actin response. These signaling pathways overlap with anti-angiogenic, extra-cellular communication and adhesion pathways. Sub-lethal concentrations of the compounds retarded both cellular migration and invasion. Anti-angiogenic and extra-cellular matrix signaling was evident with TIMP2 and P-VEGF receptor-2 upregulation. ESE-15-one and ESE-16 exhibited anti-tumor and anti-metastatic properties in vivo, using the chick chorioallantoic membrane assay. In conclusion, the sulfamoylated 2-ME analogs displayed promising anti-tumor, anti-metastatic, and anti-angiogenic properties. Future studies will assess the compounds for myeloproliferative effects, as seen in clinical applications of other drugs in this class. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced urinary bladder cancer (BCa) is characterized by rapid progression and development of therapy resistance. Despite all the available therapies, the five-year survival of metastatic BCa is a dismal 8% or lower. Many conjugates and additives of the natural polyphenol curcumin were developed and tested for potential therapeutic for cancers, with little success in vivo due to their rapid elimination and poor tissue penetrance. We tested a novel molecular hybrid CMC-2 composed of a curcumin scaffold conjugated to two dichloroacetate and glycine molecules. CMC-2 showed significantly higher antiproliferative and anti-survival activities against BCa than its parent compounds. Further, it was equally effective against chemotherapy-naïve and multidrug-resistant BCas (MDR-BCa). When tested in vivo using BCa xenograft in athymic mice, CMC-2 significantly delayed tumor growth without systemic toxicity. The mechanism of anticancer activity of CMC-2 was the induction of excessive oxidative stress in the cancer cells, leading to apoptotic cell death. These results show the potential of CMC-2 as a nontoxic oral treatment for high-grade bladder cancers. Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. [ABSTRACT FROM AUTHOR]

Introduction: The study explored the effects of SHOX2 and RASSF1A DNA methylation in lung cancer (LC). Method: Bronchoalveolar lavage fluid (BALF) samples as well as LC and normal adjacent tissues were collected from 72 LC patients and 35 patients with benign pulmonary nodules. Quantitative analysis of SHOX2 and RASSF1A DNA methylation was performed in benign pulmonary nodules and different stages of LC. The diagnostic value of SHOX2 and RASSF1A DNA methylation in LC and benign pulmonary nodules was determined by receiver operating characteristics analysis. Gain/loss-of-function experiments were constructed in LC cells and mouse models of xenograft and pulmonary nodule metastasis. The levels of SHOX2 and transfer-associated genes were tested through quantitative reverse transcription polymerase chain reaction and Western blot. Malignant phenotype of LC cells was assessed by functional experiment. The tumor volume and weight of mice in xenograft models were measured. Pulmonary nodule metastasis was determined through HE staining assay. 5-azacytidine appeared as a positive control drug. Result: SHOX2 DNA methylation or RASSF1A DNA methylation had diagnostic efficiency in pulmonary nodules and early LC, with the two combined having better diagnostic value. SHOX2 expression was upregulated in LC. Similar to 5-azacytidine, SHOX2 knockdown inhibited LC cell viability, migration, and invasion in vitro as well as restrained LC tumorigenesis and pulmonary nodule metastasis in vivo, whereas overexpressed SHOX2 had the opposite effects. Conclusion: The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early LC. SHOX2 positively modulated the tumorigenesis and metastasis of LC by regulating DNA methylation processes. [ABSTRACT FROM AUTHOR]

Objective: Lidocaine, a common local anesthetic in medical practice, exhibits anticancer properties across various tumor types. In this study, we aimed to investigate the effects and mechanisms of lidocaine on oral squamous cell carcinoma. Methods: Cell viability and proliferation were assessed through CCK‐8 and EdU assays. Transwell assays were used to analyze cell migration and invasion. Immunofluorescence assays were conducted to determine MMP9 levels. In vivo tumor growth was evaluated using a tumor xenograft model, and Ki67 and MMP9 levels were determined using immunohistochemistry. N6‐methyladenosine levels were assessed using dot plots and ELISA. mRNA and protein levels were examined through reverse transcription‐quantitative PCR or western blot analysis. The association between IGF2BP2 and caveolin‐1 was validated through RIP and luciferase reporter assays. Results: Lidocaine exhibited suppressive effects on the viability, migration, invasion, and tumor formation of oral squamous cell carcinoma. IGF2BP2 expression correlated with poor survival and was downregulated by lidocaine. Lidocaine reduced caveolin‐1 stability by decreasing IGF2BP2 levels. Caveolin‐1 overexpression partially reversed the suppressive effects of lidocaine on the progression of oral squamous cell carcinoma cells. Conclusion: Lidocaine exerts an anticancer role in oral squamous cell carcinoma via IGF2BP2‐mediated regulation of caveolin‐1 stability. [ABSTRACT FROM AUTHOR]

Considering the established pharmacokinetics and toxicity profiles, drug repurposing has emerged as an alternative therapeutic approach for treating cancer. Mefloquine has previously demonstrated inhibitory effects on multiple cancer types. This study aims to explore the impact of mefloquine on nasopharyngeal carcinoma (NPC). We found that mefloquine, at pharmacologically achievable concentrations, displayed anti-NPC activity while sparing normal counterparts. Mefloquine inhibits proliferation and induces death by reducing the levels of Cyclin A2, Bcl-2, and Bcl-xL. Intriguingly, we observed an increase in the levels of the anti-apoptotic protein Mcl-1. Mefloquine exerts its effects on NPC cells by inducing lysosomal-mediated ROS production, and the heightened expression of Mcl-1 is a consequence of ROS generation in mefloquine-treated NPC cells. The combination of an Mcl-1 inhibitor with mefloquine synergistically inhibits NPC growth in mice without causing substantial toxicity. These findings demonstrate the effectiveness and limited toxicity of mefloquine as a monotherapy and in combination with an Mcl-1 inhibitor. Our research underscores the promise of the mefloquine and Mcl-1 inhibitor combination as a potential treatment for NPC. Additionally, the elevation of Mcl-1 is a compensatory response in cells exposed to oxidative stress, offering a potential target to overcome resistance induced by pro-oxidant therapies. [ABSTRACT FROM AUTHOR]

The article offers a comprehensive update on recent advancements in diabetes research and treatments. Topics discussed include the influence of walking speed on the risk of developing type 2 diabetes, emerging evidence linking type 2 diabetes to Alzheimer's disease, and the innovative use of xenotransplantation involving pig organs to address the shortage of human kidneys for transplantation.

Background: Corneal transplantation faces significant challenges due to the shortage in donor corneas. Porcine corneas have emerged as a potential solution due to their similarities in biomechanical properties with pigs, yet xenoimmune rejection poses an obstacle to their efficacy. Methods: In this study, in silico methods were employed to analyze the compatibility of porcine corneal xenografts, focusing on two key aspects: the comparison of corneal matrix proteins and investigation of the immunological mediators and pathways involved in corneal graft rejection. The amino acid sequences of the fourteen (14) most abundant proteins in the corneal matrix were compared to determine their structural and functional differences. The primary amino acid structures and compositions, theoretical pI, and grand average of hydropathicity were determined and compared between the two species. Results: In graft performance, similarities and differences between the donor and recipient tissues influence the success of transplantation. When the proteins closely resemble each other, in terms of structural characteristics and biochemical properties, the host's immune system is less likely to recognize the tissue as foreign. The immunological mediators and pathways involved in corneal graft rejection were investigated, elucidating the mechanisms underlying xenograft incompatibility. Based on the results generated from STRING, the specific groups of molecules that are involved in the immune-mediated rejection process are costimulatory molecules, cytokines, immune checkpoint molecules, apoptosis regulators, cell adhesion molecules, growth factors, neuropeptides and hormones, certain receptors, the cytotoxic molecule GZMA, and the chemokine CCL5. Conclusions: The results of this study establish that the porcine cornea has a high suitability for corneal xenotransplantation into humans but requires immune-based therapeutic interventions to increase graft acceptance. [ABSTRACT FROM AUTHOR]

The physicochemical properties of grafting materials affect the quality of the osteointegration, resorption rate, and the new bone (NB) formation. This study assessed the physicochemical properties and integration of a low temperature deproteinized bovine bone xenograft (BBX), referred to as optimized MoaBone® (OMB). This novel BBX was physiochemically characterized both pre and post chemical bleaching and sterilization by gamma irradiation. OMB was compared to two commercial BBX; Bio‐Oss® (BO) and MoaBone® (MB) using a rabbit cranial model. Residual graft and NB were quantified using histology and micro‐computed tomography. Results showed that chemical treatment and gamma irradiation had limited effect on the surface texture. A significant decrease in the collagen content was detected post chemical treatment and in the carbonate content post gamma irradiation. There was no evidence of inflammatory infiltrate, necrosis, or connective tissue encapsulation, and a significant increase of NB in all grafted sites as compared to untreated defects could be observed. However, there was no statistically significant difference between the grafted sites. We conclude that chemical treatment and terminal sterilization strongly impact the final graft's properties. OMB graft showed equivalence with BO for in vivo bone formation and potentially results in lower levels of graft retention. [ABSTRACT FROM AUTHOR]

Objective Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC. Methods The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry. Results The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression. Conclusion Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC. [ABSTRACT FROM AUTHOR]

Background: Failure of treatment with gemcitabine in most cholangiocarcinoma (CCA) patients is due to drug resistance. The therapeutic potential of natural plant secondary compounds with minimal toxicity, such as cannabidiol (CBD), is a promising line of investigation in gemcitabine-resistant CCA. We aim to investigate the effects of CBD on gemcitabine-resistant CCA (KKU-213BGemR) cells in vitro and in vivo. Materials: In vitro, cell proliferation, colony formation, apoptosis and cell cycle arrest were assessed using MTT assay, clonogenicity assay and flow cytometry. The effect of CBD on ROS production was evaluated using the DCFH-DA fluorescent probe. The mechanism exerted by CBD on ER stress-associated apoptosis was investigated by western blot analysis. A gemcitabine-resistant CCA xenograft model was also used and the expression of PCNA and CHOP were evaluated by immunohistochemical analysis. Results: The IC50 values of CBD for KKU-213BGemR cells ranged from 19.66 to 21.05 µM. For a non-cancerous immortalized fibroblast cell line, relevant values were 18.29 to 19.21 µM. CBD suppressed colony formation by KKU-213BGemR cells in a dose-dependent manner in the range of 10 to 30 µM. CBD at 30 µM significantly increased apoptosis at early (16.37%) (P = 0.0024) and late (1.8%) stages (P < 0.0001), for a total of 18.17% apoptosis (P = 0.0017), in part by increasing ROS production (P < 0.0001). Multiphase cell cycle arrest significantly increased at G0/G1 with CBD 10 and 20 µM (P = 0.004 and P = 0.017), and at G2/M with CBD 30 µM (P = 0.005). CBD treatment resulted in increased expression of ER stress-associated apoptosis proteins, including p-PERK, BiP, ATF4, CHOP, BAX, and cytochrome c. In xenografted mouse, CBD significantly suppressed tumors at 10 and 40 mg/kg·Bw (P = 0.0007 and P = 0.0278, respectively), which was supported by an increase in CHOP, but a decrease in PCNA expression in tumor tissues (P < 0.0001). Conclusion: The results suggest that CBD exhibits potent anti-cancer activity against gemcitabine-resistant CCA in vitro and in vivo, in part via ER stress-mediated mechanisms. These results indicate that clinical explorative use of CBD on gemcitabine-resistant CCA patients is warranted. [ABSTRACT FROM AUTHOR]

Background: Studies have reported that polyphyllin I (PPI) had effective anti-tumor activity against hepatocellular carcinoma (HCC). However, the precise molecular mechanism of this action and the direct target remain unclear. The aim of this study was to discover the molecular targets and the exact mechanism of PPI in the treatment of HCC. Methods: Various HCC cells and Zebrafish xenotransplantation models were used to examine the efficacy of PPI against HCC. A proteome microarray, surface plasmon resonance (SPR) analysis, small molecule transfection, and molecular docking were conducted to confirm the direct binding targets of PPI. Transcriptome and Western blotting were then used to determine the exact responding mechanism. Finally, the anticancer effect and its precise mechanism, as well as the safety of PPI, were verified using a mouse tumor xenograft study. Results: The results demonstrated that PPI had significant anticancer activity against HCC in both in vitro studies of two cells and the zebrafish model. Notably, PPI selectively enhanced the action of the Zinc finger and BTB domain-containing 16 (ZBTB16) protein by directly binding to it. Furthermore, specific knockdown of ZBTB16 markedly attenuated PPI-dependent inhibition of HCC cell proliferation and migration caused by overexpression of the gene. The transcriptome and Western blotting also confirmed that the interaction between ZBTB16 and PPI also activated the PPARγ/RXRα pathway. Finally, the mouse experiments confirmed the efficacy and safety of PPI to treat HCC. Conclusions: Our results indicate that ZBTB16 is a promising drug target for HCC and that PPI as a potent ZBTB16 agonist has potential as a therapeutic agent against HCC by regulating the ZBTB16/PPARγ/RXRα signaling axis. [ABSTRACT FROM AUTHOR]

This article, titled "RETRACTED: MiR-1236-3p Inhibits the Proliferation, Invasion, and Migration of Colon Cancer Cells and Hinders Epithelial-Mesenchymal Transition by Targeting DCKL3," discusses a study on the role of miR-1236-3p in colon cancer. The study found that miR-1236-3p was significantly downregulated in colon cancer tissues and inhibited the proliferation, invasion, and migration of cancer cells. The researchers also identified DCKL3 as a target gene for miR-1236-3p. The study suggests that miR-1236-3p could be a promising therapeutic target for colon cancer, although further research is needed. [Extracted from the article]

Simple Summary: Combining drugs is crucial for enhancing anti-cancer responses. However, the potential of pre-clinical data in identifying suitable combinations and dosage is often underutilized. In this study, we leverage pre-clinical in vitro cell line drug response data and computational modeling of signal transduction and of pharmacokinetics to elucidate distinct dose requirements for the combination of pan-RAF and MEK inhibitors in melanoma. Our findings reveal a more synergistic but narrower dosing landscape in NRAS vs. BRAF mutant melanoma, which we link to a mechanism of adaptive resistance through negative feedback. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning. Purpose: This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. Results: In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose–response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Conclusion: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment with ARSI results in an increased expression of the TLK1B splice variant and consequent activation of the TLK1>NEK1>YAP axis. We now provide important details of the significance of the NEK1-mediated phosphorylation of the YAP-Y407F residue for its nuclear localization and transcriptional output. Furthermore, we study the effect of the pharmacologic inhibition of this pathway in a xenograft model that readily converts from androgen-dependent to castration-resistant (CRPC) prostate cancer, as a first approach to translating our work toward a clinical investigation. Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a co-activator, and pointing to the deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by stabilizing phosphorylation at Y407. We are now solidifying this work by showing the following: (1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and J54 (TLK1i) reverses this along with YAP-Y407 dephosphorylation. (2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. (3) The basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. (4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at the promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. (5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by the TMPRSS2-ERG oncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54. [ABSTRACT FROM AUTHOR]

Simple Summary: High levels of the transcription factor Grainyhead-like protein 2 (GRHL2) contribute to worse outcomes for patients with breast cancer tumors that express estrogen receptor (ER). Using multiple methods to increase GRHL2 expression in breast cancer cells, we found that high GRHL2 promotes both epithelial and mesenchymal phenotypes. This is indicative of an intermediate state between epithelial and mesenchymal cells, which is associated with metastasis. We also observed that elevated GRHL2 stimulates properties characteristic of cellular plasticity, including a decrease in cellular proliferation with a reciprocal increase in dormancy and stem cell markers. Elevated levels of GRHL2 broadly changed its control of gene expression at the level of DNA and shifted nearby transcription factor binding sites from those associated with development to those associated with disease progression. These results provide a possible explanation for how elevated GRHL2 levels could contribute to poorer prognosis in ER-positive breast cancer. Estrogen receptor (ER)-positive breast cancer is characterized by late recurrences following initial treatment. The epithelial cell fate transcription factor Grainyhead-like protein 2 (GRHL2) is overexpressed in ER-positive breast cancers and is linked to poorer prognosis as compared to ER-negative breast cancers. To understand how GRHL2 contributes to progression, GRHL2 was overexpressed in ER-positive cells. We demonstrated that elevated GRHL2 imparts plasticity with stem cell- and dormancy-associated traits. RNA sequencing and immunocytochemistry revealed that high GRHL2 not only strengthens the epithelial identity but supports a hybrid epithelial to mesenchymal transition (EMT). Proliferation and tumor studies exhibited a decrease in growth and an upregulation of dormancy markers, such as NR2F1 and CDKN1B. Mammosphere assays and flow cytometry revealed enrichment of stem cell markers CD44 and ALDH1, and increased self-renewal capacity. Cistrome analyses revealed a change in transcription factor motifs near GRHL2 sites from developmental factors to those associated with disease progression. Together, these data support the idea that the plasticity and properties induced by elevated GRHL2 may provide a selective advantage to explain the association between GRHL2 and breast cancer progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and is occurring with greater frequency worldwide. Better methods are needed to detect this disease at an early time point and help guide surgery. A peptide, or protein fragment, has been developed to bind specifically to EpCAM, a molecular target expressed uniquely by cancer cells and to concentrate in tumors. This peptide was labeled with a near-infrared fluorophore, and showed strong binding to HCC cells and in a live animal model using viable human HCC tumors. The peptide was found to be stable in serum, and showed high uptake in HCC tumors with no signs of toxicity. The peptide also bound to cancer that spread throughout the liver and into the lungs, and was more concentrated in tumors than in other organs. These results support the potential usefulness of the EpCAM peptide to detect and remove HCC. Hepatocellular carcinoma (HCC) has emerged as a major contributor to the worldwide cancer burden. Improved methods are needed for early cancer detection and image-guided surgery. Peptides have small dimensions that can overcome delivery challenges to achieve high tumor concentrations and deep penetration. We used phage display methods to biopan against the extra-cellular domain of the purified EpCAM protein, and used IRDye800 as a near-infrared (NIR) fluorophore. The 12-mer sequence HPDMFTRTHSHN was identified, and specific binding to EpCAM was validated with HCC cells in vitro. A binding affinity of kd = 67 nM and onset of k = 0.136 min−1 (7.35 min) were determined. Serum stability was measured with a half-life of T1/2 = 2.6 h. NIR fluorescence images showed peak uptake in vivo by human HCC patient-derived xenograft (PDX) tumors at 1.5 h post-injection. Also, the peptide was able to bind to foci of local and distant metastases in liver and lung. Peptide biodistribution showed high uptake in tumor versus other organs. No signs of acute toxicity were detected during animal necropsy. Immunofluorescence staining of human liver showed specific binding to HCC compared with cirrhosis, adenoma, and normal specimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite major advances in treating non-small-cell lung cancer (NSCLC), the five-year survival rates for patients without specific genetic mutations remain low. This study aims to find better ways to treat these patients. We focused on a protein called Aurora kinase A (AURKA), which our prior study suggested may play a role in modulating resistance to the common cancer drug cisplatin. We looked at how AURKA affects the sensitivity of NSCLC cells to platinum-based chemotherapy and radiation. In lab tests, AURKA levels increased after cisplatin treatment. Blocking AURKA with a drug called alisertib or using a genetic method made cisplatin and radiation more effective, causing tumors to shrink in mouse models. The treated cancer cells showed more DNA damage and underwent cell death. Blocking AURKA also increased markers that help the immune system recognize cancer. Our study suggests that combining AURKA inhibitors with other treatments could improve outcomes for NSCLC patients. Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA's role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer typically originates and metastasizes from the mammary fat pad. The tumor within the fat pad is supported by enriched lymphatic vessels, to a greater degree than that of blood vessels. Recently, we have successfully co-formulated two physically disparate cancer drugs, water-soluble gemcitabine (G) and water-insoluble paclitaxel (T), into a drug combination nanoparticle (DcNP) referred to as GT-in-DcNP. This GT-in-DcNP dosage form is stable and scalable. When it is given to mice, it enables synchronized delivery of GT into tumors via enriched lymph vessels. A single dose of GT-in-DcNP in mice has been found to suppress breast tumor growth in the mammary fat pad more effectively than an equivalent dose of the free GT combination. We observed tumor regression and restoration of mammary fat tissue at higher doses of GT-in-DcNP. This concept has been extended to demonstrate the ability to suppress human breast cancer in a xenograft model. With these observations, GT-in-DcNP may be considered for clinical development to treat breast cancer. Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small-cell lung cancer is characterized by high morbidity and mortality. Currently, the precision medicine approach in the adenocarcinoma subtype of non-small-cell lung cancer aims to identify genomic alterations that can be targeted in individual patients and offer them appropriate treatment. Several biomarker-guided therapies have been approved, targeting genes frequently altered in adenocarcinoma, such as EGFR, BRAF, MET, ALK, ROS1, RET and NTRK. To overcome the emergence of resistance and increase the efficacy of these targeted therapies, the combination of chemotherapy and targeted therapy has been studied and validated in adenocarcinoma patients with EGFR mutations. This study proposes to examine whether this type of combined approach, which is difficult to study in clinical trials, could be more widely used by targeting other genetic alterations in the MAPK/PI3K pathways or against alterations in the CDNK2A gene in adenocarcinomas but also in squamous-cell carcinomas. The combination of chemotherapy and targeted therapy has been validated in non-small-cell lung cancer (NSCLC) patients with EGFR mutations. We therefore investigated whether this type of combined approach could be more widely used by targeting other genetic alterations present in NSCLC. PDXs were generated from patients with NSCLC adenocarcinomas (ADCs) and squamous-cell carcinomas (SCCs). Targeted NGS analyses identified various molecular abnormalities in the MAPK and PI3K pathways and in the cell cycle process in our PDX panel. The antitumor efficacy of targeted therapies alone or in combination with chemotherapy was then tested in vivo. We observed that trametinib, BKM120, AZD2014 and palbociclib increased the efficacy of each chemotherapy in SCC PDXs, in contrast to a non-insignificant or slight improvement in ADCs. Furthermore, we observed high efficacy of trametinib in KRAS-, HRAS- and NRAS-mutated tumors (ADCs and SCCs), suggesting that the MEK inhibitor may be useful in a wider population of NSCLC patients, not just those with KRAS-mutated ADCs. Our results suggest that the detection of pathogenic variants by NGS should be performed in all NSCLCs, and particularly in SCCs, to offer patients a more effective combination of chemotherapy and targeted therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cancer and vascular endothelial cells. Especially, axitinib inhibits signaling via vascular endothelial growth factor receptors (VEGFRs). In this study, we report an unforeknown effect of axitinib on human lung cancer cells. We show that axitinib increased the cell size and enhanced the expression of β-galactosidase in a panel of human cancer cell lines, irrespective of their expression of VEGFRs. Especially, axitinib-treated human lung adenocarcinoma A549 cells showed typical senescence and subsequent treatment with the senolytic drug ABT-263 induced drastic cell death (senolysis). Senolysis of senescent A549 cells by ABT-263 was attributed to caspase-dependent apoptosis and Bcl-xL inhibition. Reactive oxygen species were involved in axitinib-induced senescence, but not in senolysis, of A549 cells. In an A549-xenografted mouse model, combination therapy with axitinib and ABT-263 significantly suppressed tumor growth. Background: Tyrosine kinase inhibitors (TKIs) inhibit receptor-mediated signals in cells. Axitinib is a TKI with high specificity for vascular endothelial growth factor receptors (VEGFRs). Aim: We determined whether axitinib could induce senescence in human cancer cells and be lysed by the senolytic drug ABT-263. Methods: Human lung and breast adenocarcinoma cell lines were used. These cells were cultured with axitinib or a multi-target TKI lenvatinib. The expression of β-galactosidase, VEGFRs, Ki-67, reactive oxygen species (ROS) of cancer cells, and their BrdU uptake were evaluated by flow cytometry. The mRNA expression of p21 and IL-8 was examined by quantitative PCR. The effects of TKIs on phosphorylation of Akt and Erk1/2, as downstream molecules of VEGFR signaling, were examined by immunoblot. The in vivo anti-cancer effect was examined using a xenograft mice model. Results: Axitinib, but not lenvatinib, induced cellular senescence (increased cell size and enhanced expression of β-galactosidase) in all adenocarcinoma cell lines. Axitinib-induced senescence was unrelated to the expression of VEGFRs on cancer cells. ROS were involved in axitinib-induced senescence. Axitinib-induced senescent lung adenocarcinoma A549 cells were drastically lysed by ABT-263. In A549-xenografted mice, combination therapy with axitinib and ABT-263 significantly suppressed tumor growth with the induction of apoptotic cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: As many cancers, prostate cancer is lethal when reaching the metastatic state. Starting from prostate to invade secondary sites, tumour cells undergo structural modifications called epithelial-mesenchymal transition. Molecular mechanisms controlling this phenomenon were studied in vitro and in vivo after modification of LXRs transcription factors activity, which regulate cholesterol metabolism. These studies showed that in a metastatic cell line derived from bone, increased activity of LXR stimulated the EMT processes in vitro and in vivo. We then characterized the associated deregulated genes and identified Amphiregulin as a new target regulated by LXR. The relationship between amphiregulin and EMT was here first reported in prostate cancer and as this protein can be secreted, will be further considered as a possible blood maker for monitoring metastatic occurrence. Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the "epithelial–mesenchymal transition" (EMT), which allows cells to acquire the ability to invade distant organs. Liver X Receptors (LXRs) are nuclear receptors that have been demonstrated to regulate EMT in various cancers, including hepatic cancer. Our study reveals that the LXR pathway can control pro-invasive cell capacities through EMT in prostate cancer, employing ex vivo and in vivo approaches. We characterized the EMT status of the commonly used LNCaP, DU145, and PC3 prostate cancer cell lines through molecular and immunohistochemistry experiments. The impact of LXR activation on EMT function was also assessed by analyzing the migration and invasion of these cell lines in the absence or presence of an LXR agonist. Using in vivo experiments involving NSG-immunodeficient mice xenografted with PC3-GFP cells, we were able to study metastatic spread and the effect of LXRs on this process. LXR activation led to an increase in the accumulation of Vimentin and Amphiregulin in PC3. Furthermore, the migration of PC3 cells significantly increased in the presence of the LXR agonist, correlating with an upregulation of EMT. Interestingly, LXR activation significantly increased metastatic spread in an NSG mouse model. Overall, this work identifies a promoting effect of LXRs on EMT in the PC3 model of advanced prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined. Methods: 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR. Results: This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (P < 0.014) and poor disease free survival (P < 0.042). In vitro, PYR suppressed the proliferation, colony formation and migration of OSCC cells. It also promoted apoptosis of OSCC cells and induced cell cycle arrest. Furthermore, PYR was able to inhibit the occurrence and development of OSCC effectively in vivo. Western blotting revealed that PYR suppressed OSCC by inhibiting the phosphorylation of HER2, AKT and ERK. Conclusions: This study exhibited the anti-OSCC effects of PYR in vitro and in vivo, and demonstrated PYR inhibited OSCC cells by inducing apoptosis via the HER2/ AKT and ERK pathway. The result of this study also indicated locally advanced OSCC patients might benefit from HER2 assay and EGFR/HER2 dual inhibit treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Thymomas and thymic carcinomas (together referred to as thymic epithelial tumors, TETs) are a heterogeneous group of rare tumors of the anterior mediastinum. Most treatment regimens for advanced TETs are empirical and patients have not benefited from developments in personalized medicine. We believe that one of the major unresolved problems in TET research is the lack of suitable cellular or animal models that represent the full heterogeneity of TETs, help us to study the driving mechanisms behind TET biology, and explore vulnerabilities. In this narrative review, we discuss the current state of 2D and 3D TET cell culture models and protocols. To move beyond the current state, innovative high-throughput techniques are mandatory for both systematic optimization of cell culture conditions and high-throughput drug screening. Cell culture model systems are fundamental tools for studying cancer biology and identifying therapeutic vulnerabilities in a controlled environment. TET cells are notoriously difficult to culture, with only a few permanent cell lines available. The optimal conditions and requirements for the ex vivo establishment and permanent expansion of TET cells have not been systematically studied, and it is currently unknown whether different TET subtypes require different culture conditions or specific supplements. The few permanent cell lines available represent only type AB thymomas and thymic carcinomas, while attempts to propagate tumor cells derived from type B thymomas so far have been frustrated. It is conceivable that epithelial cells in type B thymomas are critically dependent on their interaction with immature T cells or their three-dimensional scaffold. Extensive studies leading to validated cell culture protocols would be highly desirable and a major advance in the field. Alternative methods such as tumor cell organoid models, patient-derived xenografts, or tissue slices have been sporadically used in TETs, but their specific contributions and advantages remain to be shown. [ABSTRACT FROM AUTHOR]

Simple Summary: Existing treatments for pancreatic cancer have limited effectiveness due to the genetic diversity between pancreatic tumors from different patients. By propagating the original tumor into a mouse (creating a xenograft) it may be possible to study each individual tumor further and plan personalized therapy. EUS-FNA is a technique which has recently become a routine method for obtaining a biopsy from a patient without the need for surgery. In this study, we tested whether EUS-FNA can also be used to obtain tumor tissue of sufficient volume and purity to establish a corresponding xenograft and to perform a genetic analysis. We found that in the majority of cases, both mouse xenografts and genetic analyses can be performed successfully. Xenograft tumors were found to maintain the characteristics and genetic expression from the original patient tumors and to be vulnerable to infection by a virus used to destroy cancer cells. Pancreatic cancer has one of the worst prognoses among all malignancies and few available treatment options. Patient-derived xenografts can be used to develop personalized therapy for pancreatic cancer. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) may provide a powerful alternative to surgery for obtaining sufficient tissue for the establishment of patient-derived xenografts. In this study, EUS-FNA samples were obtained for 30 patients referred to the Ottawa Hospital, Ottawa, Ontario, Canada. These samples were used for xenotransplantation in NOD-SCID mice and for genetic analyses. The gene expression of pancreatic-cancer-relevant genes in xenograft tumors was examined by immunohistochemistry. Targeted sequencing of both the patient-derived tumors and xenograft tumors was performed. The xenografts' susceptibility to oncolytic virus infection was studied by infecting xenograft-derived cells with VSV∆51-GFP. The xenograft take rate was found to be 75.9% for passage 1 and 100% for passage 2. Eighty percent of patient tumor samples were successfully sequenced to a high depth for 42 cancer genes. Xenograft histological characteristics and marker expression were maintained between passages. All tested xenograft samples were susceptible to oncoviral infection. We found that EUS-FNA is an accessible, minimally invasive technique that can be used to acquire adequate pancreatic cancer tissue for the generation of patient-derived xenografts and for genetic sequencing. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we performed microdialysis in patient-derived xenografts of glioma, intending to evaluate the extracellular metabolic impacts of temozolomide, a component of standard-of-care treatment. Unexpectedly, the most striking finding in our analyses was a tumor-like metabolic signature induced by catheter insertion into a normal brain. The development of a glioma-like extracellular metabolome in the days following microdialysis catheter placement into a non-tumor-bearing brain suggests particular care is needed to accurately discriminate the longitudinal extracellular metabolomic impacts of experimental therapies from those of evolving injury-associated changes. Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury. [ABSTRACT FROM AUTHOR]