ABBV-319: a CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.

Recent advances in the aetiology of recurrent aphthous stomatitis (RAS).

Recurrent aphthous stomatitis (RAS) is the most common disease of oral mucosa, which almost attacks each individual once in their lifespan. Although plenty of factors have been suggested to play a role in the pathogenesis of RAS, the aetiology of RAS is still controversial, which might lead to limited clinical therapies in accordance with each RAS patient. This review mainly illustrates recent advances in potential causes associated with RAS in detail. Deeper comprehension of the aetiology of RAS will support doctors and researchers to make a better management of RAS patients and to discover new treatments. The aetiology of RAS is complicated, hence we should take a comprehensive view into its aetiology, with multiple potential factors being considered. Sample collection of RAS patients have greatly limited the progress in the aetiology of RAS. A research model of multiagency cooperation can help achieve perfect sample collection of year-round and multiposition.

Survival of labial inversely impacted maxillary central incisors: A retrospective cone-beam computed tomography 2-year follow-up.

INTRODUCTION: The aim of this study was to analyze the development and stability of roots and alveolar bone in orthodontically treated labial inversely impacted maxillary central incisors in a long-term follow-up by cone-beam computed tomography. Comparisons were made between the labial inversely impacted maxillary central incisors after treatment and normally erupted mature contralateral incisors. METHODS: The sample consisted of 12 participants, with a mean age of 7.80 ± 0.91 years. Cone-beam computed tomography scanning data at the completion of treatment and the long-term follow-up were available for each participant.The mean length of follow-up was 24.57 ± 4.33 months. Root length, crown height, root canal width, labial/lingual alveolar bone vertical loss, and bone thickness of the impacted and contralateral incisors were measured with the SimPlant Pro program (version 13.0; Materialise Dental, Leuven, Belgium). RESULTS: In the follow-up, the root lengths of both the labial inversely impacted dilacerated maxillary central incisors (10.99 ± 1.96 mm) and the contralateral mature maxillary central incisors (11.65 ± 1.37 mm) were significantly longer than at posttreatment (8.37 ± 1.74 mm and 9.81 ± 1.65 mm, respectively). The root canal widths of the impacted and contralateral incisors were significantly narrower during the follow-up. The size of the angle between the long axis of the crown and apical third of the root decreased significantly. The lingual alveolar bone loss of the impacted incisors was greater than that of the contralateral incisors. The labial bone thickness at the apex of the impacted incisors increased significantly during the follow-up period. CONCLUSIONS: The treated labial inversely impacted maxillary central incisors had continuous and similar growth as did the mature contralateral incisors in the follow-up period. The roots had an increase in length and a change in direction of the apex, with a relatively stable condition of the surrounding alveolar bone. Neither the labial inversely impacted maxillary central incisors nor the contralateral incisors had further alveolar bone loss.

Combined effects of proinflammatory cytokines and intermittent cyclic mechanical strain in inhibiting osteogenicity in human periodontal ligament cells.

Mechanical strain plays an important role in bone formation and resorption during orthodontic tooth movement. The mechanism has not been fully studied, and the process becomes complex with increased amounts of periodontal patients seeking orthodontic care. Our aims were to elucidate the combined effects of proinflammatory cytokines and intermittent cyclic strain (ICS) on the osteogenic capacity of human periodontal ligament cells. Cultured human periodontal ligament cells were exposed to proinflammatory cytokines (interleukin-1ß 5 ng/mL and tumor necrosis factor-α 10 ng/mL) for 1 and 5 days, and ICS (0.5 Hz, 12% elongation) was applied for 4 h per day. The autocrine of inflammatory cytokines was measured by enzyme-linked immunosorbent assay. The expression of osteoblast markers runt-related transcription factor 2 and rabbit collagen type I was determined using real-time polymerase chain reaction and Western blot. The osteogenic capacity was also detected by alkaline phosphatase (ALP) staining, ALP activity, and alizarin red staining. We demonstrated that ICS impaired the osteogenic capacity of human periodontal ligament cells when incubated with proinflammatory cytokines, as evidenced by the low expression of ALP staining, low ALP activity, reduced alizarin red staining, and reduced osteoblast markers. These data, for the first time, suggest that ICS has a negative effect on the inductive inhibition of osteogenicity in human PDL cells mediated by proinflammatory cytokines.

Early Age Shrinkage and Mechanical Effect of Ultra-High-Performance Concrete Composite Deck: A Case Study with In Situ Test and Numerical Simulation.

For the Honghe Bridge project located in Yunnan Province, Southwest China, a steel/ultrahigh-performance concrete (UHPC) composite deck is used in the suspension bridge with a 700 m main span, and the steel stud connectors are used in the 50 mm-thick UHPC layer. To investigate the shrinkage behavior of UHPC and the relevant influence, the in situ time-dependent strain is measured continuously, and within the 20-day curing time, the material behavior is summarized based on test results. This paper proposes a prediction model for UHPC shrinkage which is refined from the widely used B3 model for normal concrete material, and the parameter values are modified and optimized by experimental comparison. Combining the numerical model and the finite element analysis model of the composite deck, the detailed mechanical state in structural parts is studied. For the practical construction, the simulation results indicate that the small thickness of UHPC above the stud and weak bond strength can influence the eventual structural performance greatly. In the discussion of stress distribution at different locations of the deck, the potential crack on the edge and the corner of the UHPC-steel interface and the mechanical damage on the stud connector around are also indicated.

NUDCD1 knockdown inhibits the proliferation, migration, and invasion of pancreatic cancer via the EMT process.

NudC domain containing 1 (NUDCD1) is an oncoprotein frequently activated or upregulated in various human cancers, but its role in pancreatic cancer (PC) remains unknown. Thus, we aimed to determine the function and mechanism of NUDCD1 in PC. We employed Western blot and quantitative real-time polymerase chain reaction to assess NUDCD1 expression in cells and PC tissues. NUDCD1 was knocked down in Patu8988 and PANC-1 cells. We conducted real-time cell analysis, wound healing assay, transwell assay and colony formation assay to evaluate the metastatic and proliferative abilities of PC cells. Western blot was conducted to assess the expression of markers associated with apoptosis and epithelial-mesenchymal transition (EMT). Also, we established a tumor xenograft model to determine the role of NUDCD1 in vivo. NUDCD1 was overexpressed in PC tissues and cells. NUDCD1 knockdown suppressed the invasion, migration, and proliferative abilities of the cells and induced PC cell apoptosis. The specific mechanism of NUDCD1 was related to the modulation of the EMT process. Data obtained from in vivo experiments revealed that NUDCD1 knockdown inhibited the tumor growth, proliferation, and metastasis by modulating the EMT and inducing the apoptosis of PC cells.

A Novel Targeted Therapy System for Cervical Cancer: Co-Delivery System of Antisense LncRNA of MDC1 and Oxaliplatin Magnetic Thermosensitive Cationic Liposome Drug Carrier.

BACKGROUND: This study was aimed to prepare a novel magnetic thermosensitive cationic liposome drug carrier for the codelivery of Oxaliplatin (OXA) and antisense lncRNA of MDC1 (MDC1-AS) to Cervical cancer cells and evaluate the efficiency of this drug carrier and its antitumor effects on Cervical cancer. METHODS: Thermosensitive magnetic cationic liposomes were prepared using thin-film hydration method. The OXA and MDC1-AS vectors were loaded into the codelivery system, and the in vitro OXA thermosensitive release activity, efficiency of MDC1-AS regulating MDC1, in vitro cytotoxicity, and in vivo antitumor activity were determined. RESULTS: The codelivery system had desirable targeted delivery efficacy, OXA thermosensitive release, and MDC1-AS regulating MDC1. Codelivery of OXA and MDC1-AS enhanced the inhibition of cervical cancer cell growth in vitro and in vivo, compared with single drug delivery. CONCLUSION: The novel codelivery of OXA and MDC1-AS magnetic thermosensitive cationic liposome drug carrier can be applied in the combined chemotherapy and gene therapy for cervical cancer.

Alveolar Bone Density Reduction in Rats Caused by Unilateral Nasal Obstruction

Background: Oral breathing can cause morphological changes in the oral and maxillofacial regions. Aims: To investigate whether oral breathing affected structural changes in bone tissues. Study Design: Animal experimentation. Methods: A total of 48 8-day-old male Sprague−Dawley rats were divided into two groups: a breathing group and a sham (control) group. All Sprague−Dawley rats were killed at 7 weeks after unilateral nostril obstruction modeling. Then, structural changes in bone tissues were detected by micro-computed tomography, and the expression levels of receptor activator of nuclear factor-κB, osteoprotegerin, and receptor activator of nuclear factor-κB ligand in the signal pathway of bone metabolism within the local alveolar bone and serum of rats were detected by reverse transcription-quantitative polymerase chain reaction and Western blotting. Results: The results showed that receptor activator of nuclear factor-κB ligand and receptor activator of nuclear factor-κB levels in bone tissues and serum in the oral breathing group were higher than those in the control group [Maxillary alveolar bone: receptor activator of nuclear factor-κB ligand (pRNA=0.009, pprotein=0.008), receptor activator of nuclear factor-κB (pRNA=0.008, pprotein=0.009); Mandibular alveolar bone: receptor activator of nuclear factor-κB ligand (pRNA=0.047, pprotein=0.042), receptor activator of nuclear factor-κB (pRNA=0.041, pprotein=0.007); Serum: receptor activator of nuclear factor-κB ligand (pRNA<0.001, pprotein<0.001), receptor activator of nuclear factor-κB (pRNA<0.001, pprotein<0.001)], along with decreased osteoprotegerin expression (Maxillary alveolar bone: pRNA=0.038, pprotein=0.048; Mandibular alveolar bone: pRNA<0.001, pprotein<0.001; Serum: pRNA=0.009, pprotein=0.006) and elevated receptor activator of nuclear factor-κB ligand/osteoprotegerin. Micro-computed tomography analysis indicated a significant difference in the level of bone volume fraction, as well as trabecular thickness in maxillary alveolar bone between the experimental and control groups (p=0.049, p=0.047). Meanwhile, trabecular thickness, and cortical thickness levels in mandibular alveolar bone also differed significantly between the experimental and control groups (p=0.043, p=0.024). Conclusion: Structural changes of the respiratory system affect the alveolar bone structure and unilateral nasal obstruction may lead to a change in regional specific bone density.

[Periodontal status of labially inversely impacted maxillary central incisor in mixed dentition after orthodontic treatment].

PURPOSE: To study the periodontal status of labially inversely impacted maxillary central incisor in mixed dentition after orthodontic treatment. METHODS: Sixteen patients with labially inversely impacted maxillary central incisor in mixed dentition and treated by guided rod appliance and conventional fixed appliance were enrolled in this study. Periodontal examinations were performed and cone-beam CT (CBCT) was taken approximately 2 years post treatment. Central incisors were divided into impacted and contralateral incisor groups. Clinical examinations included plaque index (PLI), gingival index (GI), probing depth (PD), width of attached gingiva (AW) and clinical crown length (CL); Mimics 16.0 software was used to measure the length of alveolar bone around the root (ha and fc), the length from the alveolar bone crest to cemento-enamel junction(CEJ) (ab and cd) on both the labial and palatal side of the central incisors as well as the labial and palatal bone support proportion (LBP and PBP) of the root and tipping of central incisor (U1-SN). The data were analyzed using paired sample t tests with SPSS 17.0 software package. RESULTS: There was no significant difference in PLI, GI, PD, U1-SN; the value of AW, ha,fc, LBP, PBP was significantly smaller in impacted groups(P<0.01); the value of CL, ab and cd was significantly larger in impacted groups (P<0.01). CONCLUSIONS: The periodontal status of the impacted central incisor was on good condition without teeth mobility and inflammation, although a little worse than the contralateral homonymous teeth. There may be a need for periodontal bone grafting and gingival surgery in the future for the asymmetric morphology of gingiva.

A strategy for discovery of novel broad-spectrum antibacterials using a high-throughput Streptococcus pneumoniae transcription/translation screen.

The authors report the development of a high-throughput screen for inhibitors of Streptococcus pneumoniae transcription and translation (TT) using a luciferase reporter, and the secondary assays used to determine the biochemical spectrum of activity and bacterial specificity. More than 220,000 compounds were screened in mixtures of 10 compounds per well, with 10,000 picks selected for further study. False-positive hits from inhibition of luciferase activity were an extremely common artifact. After filtering luciferase inhibitors and several known classes of antibiotics, approximately 50 hits remained. These compounds were examined for their ability to inhibit Escherichia coli TT, uncoupled S. pneumoniae translation or transcription, rabbit reticulocyte translation, and in vitro toxicity in human and bacterial cells. One of these compounds had the desired profile of broad-spectrum biochemical activity in bacteria and selectivity versus mammalian biochemical and whole-cell assays.

Ribosome affinity and the prolonged molecular postantibiotic effect of cethromycin (ABT-773) in Haemophilus influenzae.

Cethromycin (ABT-773) is a new ketolide currently in clinical trials, for treatment of community acquired respiratory tract infections. The drug is active in vitro and in vivo against Haemophilus influenzae. In this study, the mechanism of action of cethromycin was investigated in H. influenzae. The drug effect was studied using in vitro transcription-translation and whole cell amino acid incorporation. Both cethromycin and erythromycin inhibit protein synthesis with similar potencies; cethromycin, however, had a prolonged molecular postantibiotic effect (PAE) compared with erythromycin which was consistent with previously reported microbiological data. Ribosome binding assay using ribosomes isolated from H. influenzae NP200 revealed that the ribosome binding affinity of cethromycin was more than 20-fold tighter than that of erythromycin. Studies of binding kinetics showed that the tight binding of cethromycin mainly contributed to the 20-fold slower dissociation from cells. Further studies showed cethromycin had a four-fold faster drug accumulation rate than erythromycin. Therefore, the tight binding of cethromycin with ribosomes likely contributed to the faster drug accumulation, slower dissociation from cells and prolonged molecular PAE of cethromycin for H. influenzae.

Electromagnetic irradiation may be a new approach to therapy for peri-implantitis.

Peri-implantitis can lead to bone destruction around a dental implant through inflammation and immune reactions caused by bacteria adhering to the surface of the implant abutment. Electromagnetic irradiation can inhibit bacterial growth, increase bone formation, decrease bone resorption and reduce the inflammatory response. Our hypothesis is that electromagnetic irradiation may be a new treatment approach for peri-implantitis and may simultaneously maintain bone mass around the dental implant. The results would be more significant when combined with other agents, because the effect of some antibiotics and anti-inflammatory drugs is strengthened by electromagnetic irradiation. This non-invasive therapy is expected to be conducted in a convenient manner, and even by patients at home, thereby facilitating the prevention and treatment of peri-implantitis.

Low level laser can be a novel adjuvant method for orthodontic tooth movement on postmenopausal women.

Osteoporosis, a pathological state commonly saw on postmenopausal women, has shown to affect jaw bone and the periodontium. While more and more adult patients seeking orthodontic treatment for a beautiful smile, the current strategy has not work well for extraction space closure in postmenopausal women with osteoporosis and concurrent bisphosphates taken. A new and non-invasive method is hoped to make a beginning. There are ample evidences showing low level laser has favorable effects on pain relief and wound healing procedure of hard and soft tissue. These effects are due to its ability to stimulate cell metabolism, angiogenesis, bone formation and osteoclastogenesis. The hypothesis we proposed herein is that low level laser may be a valuable adjuvant method for protecting and facilitating orthodontic tooth movement on this kind of patients.

Comparison of in vitro activities of ABT-773 and telithromycin against macrolide-susceptible and -resistant streptococci and staphylococci.

The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 microg/ml for ABT-773 and 0.008 to 0.06 microg/ml for telithromycin. ABT-773 had increased activities against macrolide-resistant S. pneumoniae (Erm MIC90, 0.015 microg/ml; Mef MIC90, 0.12 microg/ml) compared to those of telithromycin (Erm MIC90, 0.12 microg/ml; Mef MIC90, 1 microg/ml). Both compounds were active against strains with rRNA or ribosomal protein mutations (MIC90, 0.12 microg/ml). ABT-773 was also more active against macrolide-resistant S. pyogenes (ABT-773 Erm MIC90, 0.5 microg/ml; ABT-773 Mef MIC90, 0.12 microg/ml; telithromycin Erm MIC90, >8 microg/ml; telithromycin Mef MIC90, 1.0 microg/ml). Both compounds lacked activity against constitutive macrolide-resistant Staphylococcus aureus but had good activities against inducibly resistant Staphylococcus aureus (ABT-773 MIC90, 0.06 microg/ml; telithromycin MIC90, 0.5 microg/ml). ABT-773 has superior activity against macrolide-resistant streptococci compared to that of telithromycin.

Novel antibacterial class.

We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens.