Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.

Cleaning and Disinfecting Oval-Shaped Root Canals: Ex Vivo Evaluation of Three Rotary Instrumentation Systems with Passive Ultrasonic Irrigation.

Background and Objectives: Successful root canal treatment depends on the thorough removal of biofilms through chemomechanical preparation. This study aimed to investigate and compare the cleaning and disinfecting efficiency of oval-shaped root canals using XP-endo Shaper (XPS), ProTaper Next (PTN), and HyFlex CM (HCM) in combination with passive ultrasonic irrigation (PUI). Materials and Methods: Ninety extracted teeth were contaminated and randomly divided into three groups: XPS, PTN, and HCM. Each group was assigned to three subgroups: subgroup A (sterile saline), subgroup B (3% sodium hypochlorite and 17% ethylenediaminetetraacetic acid), and subgroup C (3% sodium hypochlorite, 17% ethylenediaminetetraacetic acid, and PUI). Bacterial sampling was conducted both from baseline samples and samples after chemomechanical preparation. Scanning electron microscopy (SEM) was used to evaluate the residue bacterial biofilms, hard tissue debris, and smear layers on the buccolingual walls of oval-shaped root canals. Results: When combined with sterile saline, XPS demonstrated a higher reduction of bacterial counts and was more effective in eradicating Enterococcus faecalis in the middle third of the canals compared to the other instruments (p < 0.05). Additionally, when used with antimicrobial irrigants, XPS was more effective in disinfecting the coronal third of the canals than the other instruments (p < 0.05). Furthermore, XPS reduced hard tissue debris more effectively in the middle third of canals than in the apical third (p < 0.05). Conclusions: XPS outperforms PTN and HCM in disinfecting oval-shaped root canals. Despite the fact that combining XPS and PUI improves cleaning and disinfecting, removing hard tissue debris from the critical apical area remains challenging.

3D Extruded Graphene Thermoelectric Threads for Self-Powered Oral Health Monitoring.

Flexible sensors play a crucial role in intelligent electronic devices, while strain-sensing is the fundamental feature for these sensors of different fields. Therefore, developing high-performance flexible strain sensors is essential for building the next generation of smart electronics. Here, a self-powered ultrasensitive strain sensor based on graphene-based thermoelectric composite threads through a simple 3D extrusion method is reported. The optimized thermoelectric composite threads show a large stretchable strain of over 800%. After 1000 cycles of bending, the threads still maintain excellent thermoelectric stability. The thermoelectric effect-induced electricity can realize ultrasensitive strain and temperature detection with high resolution. As wearable devices, the thermoelectric threads can also realize self-powered physiological signals monitoring, including the opening degree of mouth, occlusal frequency, and force of the tooth during the eating process. It provides significant judgment and guidance for promoting oral healthcare and developing good eating habits.

Mutual promotions between periodontitis and vascular calcification by rat animal model.

OBJECTIVE AND BACKGROUND: To study the relationship between periodontitis and vascular calcification by establishing rat model of chronic periodontitis and vascular calcification. METHODS: Forty male Wistar rats were divided into four groups randomly: control group, periodontitis group, vascular calcification group, and compound periodontitis and calcification group. Each group rats accepted the corresponding manages to establish the animal model. Clinical examinations and hematoxylin and eosin staining of periodontal tissue were taken to test the periodontal model; calcium assay, alkaline phosphatase activity, expression of mineral-related factors including osteopontin, alkaline phosphatase, core-binding factor-α1 and bone sialoprotein, hematoxylin and eosin staining and von Kossa staining of vascular tissue were taken to test the vascular calcification model; inflammatory factors including C-reactive protein, interleukin-1ß, tumor necrosis factor-α, interleukin-6, prostaglandin E2, and serum lipid in serum were also detected at the same time. RESULTS: The rat model was established. Inflammation of periodontal tissue and alveolar bone resorption in compound group and periodontitis group were more obvious than those in control group and vascular calcification group (P < .05). However, the calcium assay, alkaline phosphatase activity, and mineralized deposition in vascular calcification group and compound group were higher than those in control group and periodontitis group (P < .05), and compound group were the highest (P < .05); as for serum lipid, the level of total cholesterol and low-density lipoprotein-cholesterol in compound group and vascular calcification group were higher than that in control group and periodontitis group (P < .05), and compound group was the highest (P <.05); but the level of high-density lipoprotein cholesterol was higher in control group and periodontitis group. Inflammatory factors expression in serum were higher in compound group and periodontitis group, while mineral-related factors expression were higher in compoundgroup and vascular calcification group. CONCLUSION: There are some mutual promotions between periodontitis and vascular calcification, which might be related to the increasing inflammatory factors, lipids level, and mineral-related factors.

[Intramuscular type of nodular fasciitis: a report of 3 cases and review of literature].

PURPOSE: To retrospectively analyze the clinical characteristics of impacted supernumerary teeth in 115 patients. METHODS: One hundred and fifteen patients with im-pacted supernumerary teeth who were admitted to the Department of Oral and Max-illofacial Surgery of Hefei Stomatological Hospital were selected randomly. The age, sex, number of teeth, location, direction, clinical manifestation, anaes-thesia method and operation time were analyzed retrospectively, T test and Chi-square test were used to determine the statistical differences with SPSS 19.0 software package. RESULTS: Among 115 patients, there were 176 impacted supernu-merary, most of them were in mixed dentition period (66.96%), the sex ratio was 2.29:1, and Most patients (59.1%) had one supernumerary tooth, followed by two supernumerary teeth(33.9%). Most supernumerary teeth were located in the middle of the maxilla (68.2%). Inverted ones were the most common (52.8%). The most common symptoms were delayed eruption, displacement, crowding, torsion and space of the adjacent teeth. 92.2% of patients underwent general anesthesia. The dee-per the locations of impacted supernumerary were, the longer the operation time was. CONCLUSIONS: There are regional characteristics of supernumerary teeth in Hefei City, which can provide a reference for clinical diagnosis and treatment.

[Dens in dente: report of 3 cases and review of the literature].

PURPOSE: To explore the diagnosis and clinical treatment of dens in dente. METHODS: Preventive resin restoration, root canal treatment, apical barrier technique and apexification were used to treat three cases of dens in dente, respectively. The curative effects were assessed by general examinations and imageological examinations during postoperative follow-up visits. RESULTS: Three patients with different type and degree of dens in dente achieved good therapeutic effect and favorable prognosis through different treatment methods. CONCLUSIONS: Dens in dente is complex clinically and the treatment is difficult. Clinicians should improve the understanding of dens in dente. The keys to successful treatment are early diagnosis and early treatment. In addition, it is important to take proper measures according to the type and degree of dens in dente, to preserve the diseased tooth as much as possible.