Mobilan: a recombinant adenovirus carrying Toll-like receptor 5 self-activating cassette for cancer immunotherapy.

Toll-like receptor 5 (TLR5) is considered an attractive target for anticancer immunotherapy. TLR5 agonists, bacterial flagellin and engineered flagellin derivatives, have been shown to have potent antitumor and metastasis-suppressive effects in multiple animal models and to be safe in both animals and humans. Anticancer efficacy of TLR5 agonists stems from TLR5-dependent activation of nuclear factor-κB (NF-κB) that mediates innate and adaptive antitumor immune responses. To extend application of TLR5-targeted anticancer immunotherapy to tumors that do not naturally express TLR5, we created an adenovirus-based vector for intratumor delivery, named Mobilan that drives expression of self-activating TLR5 signaling cassette comprising of human TLR5 and a secreted derivative of Salmonella flagellin structurally analogous to a clinical stage TLR5 agonist, entolimod. Co-expression of TLR5 receptor and agonist in Mobilan-infected cells established an autocrine/paracrine TLR5 signaling loop resulting in constitutive activation of NF-κB both in vitro and in vivo. Injection of Mobilan into primary tumors of the prostate cancer-prone transgenic adenocarcinoma of the mouse prostate (TRAMP) mice resulted in a strong induction of multiple genes involved in inflammatory responses and mobilization of innate immune cells into the tumors including neutrophils and NK cells and suppressed tumor progression. Intratumoral injection of Mobilan into subcutaneously growing syngeneic prostate tumors in immunocompetent hosts improved animal survival after surgical resection of the tumors, by suppression of tumor metastasis. In addition, vaccination of mice with irradiated Mobilan-transduced prostate tumor cells protected mice against subsequent tumor challenge. These results provide proof-of-concept for Mobilan as a tool for antitumor vaccination that directs TLR5-mediated immune response toward cancer cells and does not require identification of tumor antigens.

Functional genetics-directed identification of novel pharmacological inhibitors of FAS- and TNF-dependent apoptosis that protect mice from acute liver failure.

shRNA-mediated gene-silencing technology paired with cell-based functional readouts reveals potential targets directly, providing an opportunity to identify drugs against the target without knowing the precise role of the target in the pathophysiological processes of interest. By screening a lentiviral shRNA library targeting for major components of human signaling pathways and known drug targets, we identified and validated both canonical as well as 52 novel mediators of FAS and TNF ligand-induced apoptosis. Presence of potential therapeutic targets among these mediators was confirmed by demonstration of in vivo activity of siRNAs against four identified target candidates that protected mice from acute liver failure (ALF), a life-threatening disease with known involvement of death receptor (DR)-mediated apoptosis. Network-based modeling was used to predict small-molecule inhibitors for several candidate apoptosis mediators, including somatostatin receptor 5 (SSTR5) and a regulatory subunit of PP2A phosphatase, PPP2R5A. Remarkably, pharmacological inhibition of either SSTR5 or PPP2R5A reduced apoptosis induced by either FASL or TNF in cultured cells and dramatically improved survival in several mouse models of ALF. These results demonstrate the utility of loss-of-function genetic screens and network-based drug-repositioning methods for expedited identification of targeted drug candidates and revealed pharmacological agents potentially suitable for treatment of DR-mediated pathologies.

Impression procedure for patients with severely limited mouth opening.

Patients with limited mouth opening are a common occurrence in prosthodontic practice. The majority of these patients can be treated with exercise and stretching movements before impressions are made. Some will not respond to these procedures because of facial scarring and surgical manipulation of the facial muscles. This article presents an impression procedure for overcoming such reduced mouth opening.

A case report of subpontic osseous hyperplasia in the maxillary arch.

Subpontic osseous hyperplasia has been portrayed in both the historical and the current literature as occurring exclusively in the mandibular posterior region. This article presents the clinical, radiologic, and microscopic documentation of subpontic osseous hyperplasia occurring in the maxillary first molar region.

Water immersion procedure for making light-cured custom trays with wax spacers.

This article describes a modified light-curing method that minimizes wax spacer heating and distortion. In addition, this method eliminates the need for tinfoil adaptation or use of a coating to make an air barrier in the fabrication of light-cured custom trays for removable prosthodontics.

Synergistic relationship between luting and priming agents and gold restorations plated with stannic oxide.

Bonding to dentin and enamel has increased restorative treatment options, provided the materials are used to optimum advantage. Restorative dentists must understand the indications and the proper mechanisms for using these materials. As with many techniques and procedures, it takes more time to describe than to accomplish. The tooth-conditioning and cementing steps are standard treatment procedures used daily in most dental offices. Tin-plating and preparing the metal surface are laboratory procedures and consume no chair time. The clinical advantages of bonding--such as resistance to microleakage and recurring decay, enhanced retention, preservation of tooth structure, and extended restoration prognosis--far outweigh the modest increase in placement time.

Compositional influence on the strength of dental porcelain.

This work compared the tensile strength of two glass compositions with published values of currently available dental porcelains. The influence of several variables, such as air and vacuum firing, firing temperature, surface roughness, immersion in water, and the inclusion of filler particles, on the inherent strength of the glass compositions is also discussed. The authors developed a glass frit having a tensile strength of 102.4 MPa as determined by the biaxial flexure technique. This value compares favorably with the reported strength of commercial brands of feldspathic porcelains. The strength of this glass was not significantly reduced as a result of surface abrasion or immersion in distilled water.

Infection control in a prosthodontic residency program.

Awareness of the need to incorporate an effective infection control program within a prosthodontic practice requires the faculty of a prosthodontic residency program to present a clear and workable model that will allow the flexibility necessary to accommodate the changes in infection control procedures and materials. The use of the barrier system to insulate the operatory, resident, faculty, and dental laboratory is discussed. Current disinfection and sterilization methods used to maintain the barriers are recommended.

Simplifying the altered cast impression technique for distal-extension removable partial dentures.

This technique allows construction of a detachable custom tray by the dental laboratory before the distal extension RPD framework is returned to the dentist. This permits a framework try-in with unencumbered physiologic relief, rapid attachment of the custom tray, subsequent impression making, and possibly jaw relation records all in one patient visit.

Positional accuracy of four die tray systems.

This study evaluated the positional accuracy of dies with four die tray systems. The die trays were: (1) Accu*trac Precision die system, (2) Model-Tray system, (3) Sterdo Split model tray, and (4) Tricodent One*Cast die tray system. Positional change of the dies was measured by using an Olympus binocular scanning tunneling microscope (STM). Positional change of the dies was the difference between preremoval and postremoval die position. Results show that all four die tray systems are not significantly different in most measurement categories, although the Model-Tray system was significantly different from the other die tray systems in one measurement category.

Effect of apical resections and reverse fillings on Thermafil root canal obturations.

This in vitro dye leakage study examined the influence of apical root resection and reverse amalgam fillings on the apical seal of root canals obturated with Thermafil. Fifty human canine teeth were instrumented and obturated with either laterally condensed gutta-percha or Thermafil using Roth's zinc oxide-eugenol Type I regular sealer. After 24 h, one of the following additional procedures was performed on 30 of the teeth: 2-mm apical resection, 4-mm apical resection, and 2-mm apical resection plus reverse amalgam filling 2 mm in depth and diameter. The external root surfaces were coated with enamel paint and the teeth were exposed to 1% methylene blue dye at 37 degrees C for 2 wk. The roots were split longitudinally and the depth of linear dye penetration was measured through a stereozoom microscope. Statistical analysis showed no significant differences in the linear dye penetration among the various groups of teeth.

The efficacy of four root canal obturation techniques in preventing apical dye penetration.

This study compared the average apical dye penetration observed after obturation with four root canal gutta-percha obturation techniques. Two thermoplasticized techniques were the most effective of the four methods tested.

Description of semantic--syntactic relations in an autistic child.

This longitudinal study investigated the language acquisition strategies employed by an autistic child learning sign language. The child's core vocabulary and developing semantic-syntactic relationships were compared with language acquisition in normal children. There were specific deviations in language development noted, in spite of providing the child with appropriate sign language training.