Canine Histiocytic and Hemophagocytic Histiocytic Sarcomas Display KRAS and Extensive PTPN11/SHP2 Mutations and Respond In Vitro to MEK Inhibition by Cobimetinib.

Histiocytic sarcoma (HS) is a rare and highly aggressive cancer in humans and dogs. In dogs, it has a high prevalence in certain breeds, such as Bernese mountain dogs (BMDs) and flat-coated retrievers. Hemophagocytic histiocytic sarcoma (HHS) is a unique form of HS that presents with erythrophagocytosis. Due to its rareness, the study of HHS is very limited, and mutations in canine HHS patients have not been studied to date. In previous work, our research group identified two major PTPN11/SHP2 driver mutations, E76K and G503V, in HS in dogs. Here, we report additional mutations located in exon 3 of PTPN11/SHP2 in both HS and HHS cases, further supporting that this area is a mutational hotspot in dogs and that mutations in tumors and liquid biopsies should be evaluated utilizing comprehensive methods such as Sanger and NextGen sequencing. The overall prevalence of PTPN11/SHP2 mutations was 55.8% in HS and 46.2% in HHS. In addition, we identified mutations in KRAS, in about 3% of HS and 4% of HHS cases. These findings point to the shared molecular pathology of activation of the MAPK pathway in HS and HHS cases. We evaluated the efficacy of the highly specific MEK inhibitor, cobimetinib, in canine HS and HHS cell lines. We found that the IC50 values ranged from 74 to 372 nM, which are within the achievable and tolerable ranges for cobimetinib. This finding positions cobimetinib as a promising potential candidate for future canine clinical trials and enhances our understanding of the molecular defects in these challenging cancers.

Evaluation of the clinical application of personalized 3D printing and CAD/CAM resin crowns to replace stainless steel crowns in paediatric dentistry.

BACKGROUND: Children with dental caries are treated with stainless steel metal crowns (SSC), but the aesthetics and precision still need to be improved. Currently, both 3D-printed resin crowns (PRC) and computer-aided design/computer-aided manufacture (CAD/CAM) resin crowns (CRC) meet the clinical requirements for crown applications in terms of strength, production time, cost, and aesthetics. AIM: This study replaced SSC with customized resin crowns by 3D printing and CAD/CAM. DESIGN: In this study, PRC, CRC, and SSC were used for incisor and molar restorations, and 60 crowns were made with 10 for each group. The fabrication efficiency, surface characteristics, marginal fit, and stability of the two different crowns were evaluated. RESULTS: PRC and CRC show superior color and surface characteristics, though production times are longer (5.3-12.4 times and 3.3-9.1 times, respectively) than for SSC (p < .05). They, however, can be completed within 80 min. Edge gaps for PRC and CRC are significantly lower (13.0-19.2 times and 13.0-13.7 times) than for SSC (p < .05). All materials exhibit good stability. CONCLUSION: The 3D-PRCs and CAD/CAM resin crowns may replace SSCs as a potential choice for clinical child caries.

UB-612 pan-SARS-CoV-2 T cell immunity-promoting vaccine protects against COVID-19 moderate-severe disease.

UB-612 pan-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine targets the monomeric Spike S1-receptor binding domain (RBD) subunit protein along with five sequence-conserved T cell epitopes found on Spike S2 and non-Spike M and N proteins. UB-612 vaccination safely induces potent, broad, and long-lasting immunity against SARS-CoV-2. A phase-2 trial-extended observational study during the Omicron BA.2-/BA.5-dominated outbreak was conducted to investigate UB-612's protective effect against COVID-19 hospitalization and intensive care unit (ICU) admission (H-ICU). Additionally, memory viral-neutralizing titer and T cell immunity behind disease protection were explored. No cases of H-ICU were reported beyond 14 months post-second dose or beyond 10 months post-booster (third dose). The positive outcome correlates with strong cytotoxic CD8 T cell immunity, in line with the results of an ongoing phase-3 heterologous booster trial showing that UB-612 can enhance anti-BA.5 seroconversion rate and viral-neutralizing titer for mRNA, adeno-vectored, and virus-inactivated vaccine platforms. The UB-612 multitope vaccine may serve as an effective primer and booster for those at risk of SARS-CoV-2 infection.

Research progress of ginger in the treatment of gastrointestinal tumors.

Cancer seriously endangers human health. Gastrointestinal cancer is the most common and major malignant tumor, and its morbidity and mortality are gradually increasing. Although there are effective treatments such as radiotherapy and chemotherapy for gastrointestinal tumors, they are often accompanied by serious side effects. According to the traditional Chinese medicine and food homology theory, many materials are both food and medicine. Moreover, food is just as capable of preventing and treating diseases as medicine. Medicine and food homologous herbs not only have excellent pharmacological effects and activities but also have few side effects. As a typical medicinal herb with both medicinal and edible uses, some components of ginger have been shown to have good efficacy and safety against cancer. A mass of evidence has also shown that ginger has anti-tumor effects on digestive tract cancers (such as gastric cancer, colorectal cancer, liver cancer, laryngeal cancer, and pancreatic cancer) through a variety of pathways. The aim of this study is to investigate the mechanisms of action of the main components of ginger and their potential clinical applications in treating gastrointestinal tumors.

Harnessing Nuclear Energy to Gold Nanoparticles for the Concurrent Chemoradiotherapy of Glioblastoma.

Nuclear fission reactions can release massive amounts of energy accompanied by neutrons and γ photons, which create a mixed radiation field and enable a series of reactions in nuclear reactors. This study demonstrates a one-pot/one-step approach to synthesizing radioactive gold nanoparticles (RGNP) without using radioactive precursors and reducing agents. Trivalent gold ions are reduced into gold nanoparticles (8.6-146 nm), and a particular portion of 197Au atoms is simultaneously converted to 198Au atoms, rendering the nanoparticles radioactive. We suggest that harnessing nuclear energy to gold nanoparticles is feasible in the interests of advancing nanotechnology for cancer therapy. A combination of RGNP applied through convection-enhanced delivery (CED) and temozolomide (TMZ) through oral administration demonstrates the synergistic effect in treating glioblastoma-bearing mice. The mean survival for RGNP/TMZ treatment was 68.9 ± 9.7 days compared to that for standalone RGNP (38.4 ± 2.2 days) or TMZ (42.8 ± 2.5 days) therapies. Based on the verification of bioluminescence images, positron emission tomography, and immunohistochemistry inspection, the combination treatment can inhibit the proliferation of glioblastoma, highlighting the niche of concurrent chemoradiotherapy (CCRT) attributed to RGNP and TMZ.

The mechanism of dehydroandrographolide inhibiting metastasis in gastric cancer based on network pharmacology and bioinformatics.

Gastric cancer (GC) is the most aggressive malignant tumor of the digestive tract. However, there is still a lack of effective treatment methods in clinical practice. Studies have shown that dehydroandrographolide (DA) has been shown to have anti-cancer activity in a variety of cancers, but it has not been reported in GC. Firstly, we obtained data on DA target genes, GC-related genes, and differentially expressed genes (DEGs) from the PharmMapper, GeneCards, and GEO databases, respectively. Then, the STRING database was used to construct the protein-protein interaction network of intersection genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of intersection genes were performed. Finally, 8 hub target genes were identified by analyzing their expression and prognostic survival, and molecular docking between the hub genes and DA was performed. In this study, 293 DA drug target genes, 11,366 GC-related genes, and 3184 DEGs were identified. Gene Ontology and KEGG analysis showed that the intersection genes of DA targets and GC-related genes were mainly related to cancer pathways involving apoptosis and cell adhesion. The intersection genes of DEGs, DA targets, and GC-related genes were also mainly related to cancer pathways involving chemical carcinogenesis, and drug metabolism. The molecular docking results showed that the 8 hub target genes had an apparent affinity for DA, which could be used as potential targets for DA treatment of GC. The results of this study show that the molecular mechanism by which DA inhibits GC metastasis involves multiple target genes. It may play an essential role in inhibiting the invasion and metastasis of GC by regulating the expression and polymorphism of hub target genes, such as MMP9, MMP12, CTSB, ESRRG, GSTA1, ADHIC, CA2, and AKR1C2.

Risk factors related with avascular necrosis after internal fixation of femoral neck fractures in children: a systematic review and meta-analysis.

Background: Less than 1% of children develop femoral neck fractures (FNF), making them uncommon. However, they may have dangerous side effects, like avascular necrosis. Even though several risk factors for postoperative avascular necrosis have been identified, there is still debate regarding them. In this investigation, a meta-analysis was performed to examine the potential causes of postoperative avascular necrosis in children with FNF. Methods: We conducted a thorough literature search to find risk factors for avascular necrosis (AVN) after internal fixation of pediatric FNF. Until December 2022, we searched several databases, including PubMed, Embase, Cochrane Library, Web of Science, CNKI, Orthosearch, and Sinomed. Software Zotero 6.0 and Stata 17.0 were used to organise and synthesise the data. Finally, a sensitivity and publication bias test was carried out. Results: Our study includes a total of 15 case-control studies involving 814 patients. The risk of postoperative AVN increased with age at fracture encounter (95% CI: 0.64-1.88, P = 0.0003), initial fracture displacement (95% CI: 1.87-9.54, P = 0.0005), and poor fracture reduction (95% CI:1.95-22.34, P = 0.0024) were risk factors for postoperative AVN. There was no significant relationship between gender and postoperative AVN (95% CI: 0.52-1.31, P = 0.41). Conversely, Postoperative AVN and reduction methods have no connection with each other (95% CI: 0.77-2.66, P = 0.25), procedure time (95% CI: 0.43-2.99, P = 0.16), or injury mechanism (95% CI: 0.32-2.26, P = 0.75). The incidence of post-operative AVN varies between Delbet fracture types (95% CI: 0.15-0.31, P < 0.0001), with the overall trend being that the incidence of post-operative AVN is highest for type II, lowest for type IV, and close for types I and III, but it is not clear which type of fracture is the independent risk factor. Funnel plots indicate no significant publication bias. Conclusions: In line with this study, About 26% of children who underwent surgery for a femoral neck fracture suffered postoperative AVN. The main risk factors for AVN were the child's age, the initial displacement of the fractures, and poorly reduced fractures. The risk of AVN did not significantly correlate with gender, the time of the procedure, reduction methods or the mechanism of injury. The overall trend in the incidence of postoperative AVN for the different Delbet types of fracture is that the incidence of postoperative AVN is highest for type II, lowest for type IV, and close for types I and III, but it is not clear which type of fracture is the independent risk factor.

MiR-204-3p overexpression inhibits gastric carcinoma cell proliferation by inhibiting the MAPK pathway and RIP1/MLK1 necroptosis pathway to promote apoptosis.

BACKGROUND: Gastric carcinoma (GC) is the third most frequent cause of cancer-related death, highlighting the pressing need for novel clinical treatment options. In this regard, microRNAs (miRNAs) have emerged as a promising therapeutic strategy. Studies have shown that miRNAs can regulate related signaling pathways, acting as tumor suppressors or tumor promoters. AIM: To explore the effect of miR-204-3p on GC cells. METHODS: We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction, followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells. CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells, and the colony formation ability of GC cells was detected by the clonal formation assay. The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry. The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells. Furthermore, the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway, necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques. RESULTS: Firstly, we found that the expression of miR-204-3p in GC was low. When treated with the lentivirus overexpression vector, miR-204-3p expression significantly increased, but the lentivirus knockout vector had no significant effect on miR-204-3p. In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability, promoted cell apoptosis, blocked the cell cycle, and inhibited colony formation ability. In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice. Simultaneously, our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway, as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway. CONCLUSION: MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells. Thus, miR-204-3p may represent a new potential therapeutic target for GC.

The running barbed tension-offloading suture: An updated technique update on tension wound closure.

TECHNIQUE: The CHN•WU wound suture technique uses barbed sutures. The needle is inserted from the basal part of the superficial fascia at the left edge of the wound and passed through half of the reticular dermis to reach a point (1A) approximately 0.5-2 cm away from the wound edge. Occlusion is achieved at 1A at the level of the reticular dermis, and if done correctly, a shallow concavity will appear at the occlusion point on the skin. The needle is then walked along the natural curvature until it reaches the center of the wound and then moved out from the junction between the dermis and subcutaneous tissue. On the other side of the incision, the needle is inserted into the contralateral position at the junction between the dermis and subcutaneous tissue and moved along its natural curvature to achieve occlusion at the mirror site of 1A in the reticular dermis. This process is repeated until the entire wound is closed. In the end, two stitches should be applied in the opposite direction. The left barbed suture is cut and thrown. RESULTS: This technique does not break through the epidermis, has high suture efficiency and satisfactory cosmetic appearance, disperses mechanical tension, and maintains wound tensile strength. CONCLUSION: This technique was especially effective in closing high-tension wounds in the chest and extremities where the blood supply to both sides of the wound was not affected after suturing, and wound closure could be performed quickly and efficiently in one stage.

Cartilaginous predictors of residual acetabular dysplasia (RAD) in developmental dysplasia of the hip following closed or open reduction: A systematic review and meta-analysis.

Object: This study was designed to analyze the cartilaginous predictors of residual acetabular dysplasia (RAD) after early treatment of developmental dysplasia of the hip and their diagnostic accuracy. Study design: Databases such as PubMed, Embase, Cochrane, and Web of science were searched to screen the literature. The quality of the literature was assessed by the QUADAS-2 tool. Qualitative and quantitative synthesis of literature were performed based on extracted data. For quantitative synthesis studies, the sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve with corresponding confidence intervals were calculated. Results: For the cartilaginous acetabular index (CAI) group, the combined values of sensitivity, specificity, and DOR were 0.80 (95% CI = 0.54-0.93), 0.73 (95% CI = 0.57-0.84), and 10.62 (95% CI = 3.96-28.53), respectively. The corresponding values in the cartilaginous center-edge angle (CCE) group were 0.71 (95% CI = 0.57-0.82), 0.78 (95% CI = 0.66-0.87), and 8.64 (95% CI = 3.08-24.25), respectively. The area under the curve (AUC) of SROC was 0.82 (95% CI = 0.78-0.85) and 0.80 (95% CI = 0.76-0.83) for the CAI and CCE groups. The CAI group had higher sensitivity, DOR, and AUC than the CCE group. Conclusion: Both of these two groups have good diagnostic accuracy, and CAI/L-AI has a little edge over CCE/L-CEA. However, there is still more research needed to determine whether they can be used as independent indications for secondary orthopedic surgery.Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier: [CRD42022338332].

Laser Combined with Radiotherapy for Keloid Treatment: A Novel and Efficient Comprehensive Therapy with a Lower Recurrence Rate.

BACKGROUND: Keloids are a fibroproliferative skin disorder with a high recurrence rate. Combined therapies are often used in clinical treatment, but, in addition to the relatively high risk of relapse and complexity of the treatment process, side effects remain unknown for combination therapies. METHODS: A total of 99 patients with keloids in 131 positions were included in this retrospective study. Fractional CO 2 laser therapy was first applied with energy ranging from 360 to 1008 mJ; then, 6-Mev, 900-cGy electron beam irradiation was applied twice. The first pass was initiated within 24 hours after the laser therapy, and the second pass was performed on the seventh day after laser therapy. The Patient and Observer Scar Scale evaluated the lesions before the treatment and at 6, 12, and 18 months after treatment. At each follow-up visit, the patients filled out a questionnaire on recurrence, side effects, and satisfaction. RESULTS: The authors found a significant decrease in total Patient and Observer Scar Scale score [29 (23, 39) versus 61.2 ± 13.4; P < 0.001] at the 18-month follow-up compared with the baseline value (before the therapy). A total of 12.1% of the patients had recurrences during the 18-month follow-up period (11.1% partial recurrence and 1.0% complete recurrence). The total satisfaction rate was 97.0%. No severe adverse effects were observed during the follow-up period. CONCLUSIONS: Laser combined with radiotherapy is a new comprehensive therapy comprising ablative lasers and radiotherapy for keloids. It had excellent clinical efficacy, low recurrence rate, and no serious adverse effects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Anti-tumor effect of coix seed based on the theory of medicinal and food homology.

Coix seed is a dry and mature seed of Coix lacryma-jobi L.var.ma-yuen (Roman.) Stapf in the Gramineae family. Coix seed has a sweet, light taste, and a cool nature. Coix seed enters the spleen, stomach, and lung meridians. It has the effects of promoting diuresis and dampness, strengthening the spleen to prevent diarrhea, removing arthralgia, expelling pus, and detoxifying and dispersing nodules. It is used for the treatment of edema, athlete's foot, poor urination, spleen deficiency and diarrhea, dampness and obstruction, lung carbuncle, intestinal carbuncle, verruca, and cancer. The medicinal and health value is high, and it has been included in the list of medicinal and food sources in China, which has a large development and application space. This article reviews the current research achievements in the processing methods and anti-tumor activities of Coix seed and provides examples of its clinical application in ancient and modern times, aiming to provide reference for further research on Coix seed and contribute to its clinical application and development. Through the analysis of the traditional Chinese patent medicines, and simple preparations and related health food of Coix seed queried by Yaozhi.com, the source, function, and dosage form of Coix seed were comprehensively analyzed, with a view of providing a reference for the development of Coix seed medicine and food.

Establishment and Characterization of Cell Lines from Canine Metastatic Osteosarcoma.

Despite the advancements in treatments for other cancers, the outcomes for osteosarcoma (OSA) patients have not improved in the past forty years, especially in metastatic patients. Moreover, the major cause of death in OSA patients is due to metastatic lesions. In the current study, we report on the establishment of three cell lines derived from metastatic canine OSA patients and their transcriptome as compared to normal canine osteoblasts. All the OSA cell lines displayed significant upregulation of genes in the epithelial mesenchymal transition (EMT) pathway, and upregulation of key cytokines such as CXCL8, CXCL10 and IL6. The two most upregulated genes are MX1 and ISG15. Interestingly, ISG15 has recently been identified as a potential therapeutic target for OSA. In addition, there is notable downregulation of cell cycle control genes, including CDKN2A, CDKN2B and THBS1. At the protein level, p16INK4A, coded by CDKN2A, was undetectable in all the canine OSA cell lines, while expression of the tumor suppressor PTEN was variable, with one cell line showing complete absence and others showing low levels of expression. In addition, the cells express a variety of actionable genes, including KIT, ERBB2, VEGF and immune checkpoint genes. These findings, similar to those reported in human OSA, point to some genes that can be used for prognosis, targeted therapies and novel drug development for both canine and human OSA patients.

Long-term fasting glucose variability and risk of cancer in patients with type 2 diabetes mellitus: A retrospective population-based cohort study in Shanghai.

BACKGROUNDS: Fasting blood glucose (FBG) variability may make an impact on adverse events in patients with diabetes mellitus. However, the association between long-term changes in FBG and cancer remains unclear. We aimed to investigate this association in a large-scale longitudinal study. METHODS: Data were collected from 46 761 patients with type 2 diabetes mellitus aged 20-80 years who participated in the Diabetes Standardized Management Program in Shanghai, China. We adopted four indicators, including standard deviation (SD), coefficient of variation (CV), variation independent of the mean (VIM), and average real variability (ARV) to describe FBG variability. Adjusted multivariable Cox regression analyses and restricted cubic splines were used to investigate the association between long-term FBG variability and cancer risk. We also determined the interactive effect of FBG variability with hypertension and FBG-mean with hypertension on cancer risk, respectively. RESULTS: In this study, we confirmed 2218 cancer cases (51.1% male) over a median follow-up of 2.86 years. In the multivariable-adjusted models, participants in the highest quartile of FBG variability had an increased risk of cancer compared with those in the lowest quartile. The nonlinear association was found when using FBG-VIM, FBG-ARV, and FBG-SD in restricted cubic spline plots. There was a significant interaction effect of FBG variability with hypertension on cancer, whereas the effect of FBG-mean with hypertension did not attain significance. CONCLUSIONS: Our retrospective cohort study demonstrated a positive association between the long-term changes in FBG and cancer risk in patients with type 2 diabetes mellitus. FBG variability may independently predict cancer incidence.

Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs.

Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA.

Sorafenib and Doxorubicin Show Synergistic Effects in Human and Canine Osteosarcoma Cell Lines.

Osteosarcoma (OSA) is the most common bone tumor in both humans and dogs and has a nearly ten-fold higher incidence in dogs than humans. Despite advances in the treatment of other cancers, the overall survival rates for OSA have stagnated for the past four decades. Therefore, there is a great need to identify novel and effective treatments. We screened a series of tyrosine kinase inhibitors and selected sorafenib, a multi-kinase inhibitor, for further evaluation alone and in combination with cisplatin, carboplatin, and doxorubicin on canine and human OSA cell lines. Our data point to synergistic effects when sorafenib is combined with doxorubicin, but not when combined with cisplatin or carboplatin, in both human and canine OSA. Based on current findings, clinical trials using a combination of doxorubicin and sorafenib in proof-of-concept studies in dogs are warranted. These studies can be carried out relatively quickly in dogs where case load is high and, in turn, provide useful data for the initiation of clinical trials in humans.

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma.

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.

Genetic co-expression networks contribute to creating predictive model and exploring novel biomarkers for the prognosis of breast cancer.

Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10-8) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.

Infrapatellar Fat Pads-Derived Stem Cell Is a Favorable Cell Source for Articular Cartilage Tissue Engineering: An In Vitro and Ex Vivo Study Based on 3D Organized Self-Assembled Biomimetic Scaffold.

OBJECTIVE: Adipose tissue-derived stem cells (ASCs) are a promising source of cells for articular cartilage regeneration. However, ASCs isolated from different adipose tissue depots have heterogeneous cell characterizations and differentiation potential when cultured in 3-dimensional (3D) niches. DESIGN: We compared the chondrogenicity of ASCs isolated from infrapatellar fat pads (IPFPs) and subcutaneous fat pads (SCFPs) in 3D gelatin-based biomimetic matrix. RESULTS: The IPFP-ASC-differentiated chondrocytes had higher ACAN, COL2A1, COL10, SOX6, SOX9, ChM-1, and MIA-3 mRNA levels and lower COL1A1 and VEGF levels than the SCFP-ASCs in 3D matrix. The difference in mRNA profile may have contributed to activation of the Akt, p38, RhoA, and JNK signaling pathways in the IPFP-ASCs. The chondrocytes differentiated from IPFP-ASCs had pronounced glycosaminoglycan and collagen type II production and a high chondroitin-6-sulfate/chondroitin-4-sulfate ratio with less polymerization of ß-actin filaments. In an ex vivo mice model, magnetic resonance imaging revealed a shorter T2 relaxation time, indicating that more abundant extracellular matrix was secreted in the IPFP-ASC-matrix group. Histological examinations revealed that the IPFP-ASC matrix had higher chondrogenic efficacy of new cartilaginous tissue generation as evident in collagen type II and S-100 staining. Conclusion. ASCs isolated from IPFPs may be better candidates for cartilage regeneration, highlighting the translational potential of cartilage tissue engineering using the IPFP-ASC matrix technique.