Generation and characterization of potential dengue vaccine candidates based on domain III of the envelope protein and the capsid protein of the four serotypes of dengue virus

Dengue is currently one of the most important arthropod-borne diseases, causing up to 25,000 deaths annually. There is currently no vaccine to prevent dengue virus infection, which needs a tetravalent vaccine approach. In this work, we describe the cloning and expression in Escherichia coli of envelope domain III-capsid chimeric proteins (DIIIC) of the four dengue serotypes as a tetravalent dengue vaccine candidate that is potentially able to generate humoral and cellular immunity. The recombinant proteins were purified to more than 85 % purity and were recognized by anti-dengue mouse and human sera. Mass spectrometry analysis verified the identity of the proteins and the correct formation of the intracatenary disulfide bond in the domain III region. The chimeric DIIIC proteins were also serotype-specific, and in the presence of oligonucleotides, they formed aggregates that were visible by electron microscopy. These results support the future use of DIIIC recombinant chimeric proteins in preclinical studies in mice for assessing their immunogenicity and efficacy.     

First description of hemagglutination by a virus belonging to the family Dicistroviridae

Triatoma virus is the only virus whose genome has been sequenced and studied in triatomines. It belongs to the family Dicistroviridae. In order to detect whether TrV has the ability to agglutinate erythrocytes of domestic and laboratory animals, we performed a hemagglutination assay. Positive hemagglutination was found for red blood cells of guinea pigs. The HA assay could be used as a titration method, at least for purified viral particles obtained from triatomine stool. This is the first record of hemagglutinating properties for Dicistroviridae.     

Biomechanical and histological evaluation of four different titanium implant surface modifications: an experimental study in the rabbit tibia

Objectives

This study presents a biomechanical comparison of bone response to commercially pure titanium screws with four different types of surface topographies placed in the tibial metaphysis of 30 rabbits.

Materials and methods

One hundred twenty implants were tested double-blinded: (a) blasted, acid-etched, and discrete crystal deposition (DCD), (b) blasted, (c) acid-etched, and (d) blasted and acid-etch. Resonance frequency analysis (RFA/ISQ), reverse torque values (RTV), and bone-to-implant contact (BIC) were measured at the time of implant insertion (day 0), 15, 28, and 56 days of healing.

Results

All groups tested demonstrated increased RFA/ISQ and RTV results over the time course. At 15 days, the blasted, acid-etched, and DCD group demonstrated a non-significant trend toward higher values when compared to the blasted and etched group (33.0?±?16 vs. 26.3?±?12 Ncm, p?=?.16). At 56 days, the groups utilizing blasting to create additional surface roughness (Sa?>?1 micron) showed a statistical significant difference in RTQ versus the non-blasted group (38.5?±?14 vs. 29.5?±?9 Ncm, p?=?.03).

Conclusions

Within the limitations of this study, only the increase in surface roughness (Ra?>?1) at 56 days demonstrated statistically significant effects on RTQ. Other additional surface features, such as sub-micron scale DCD, demonstrated improved healing trends but without significance for clinical applications.     

Phospho-Aspirin (MDC-22) inhibits pancreatic cancer growth in patient-derived tumor xenografts and KPC mice by targeting EGFR: Enhanced efficacy in combination with irinotecan

Novel therapeutic strategies are needed in the fight against pancreatic cancer. We have previously documented the chemopreventive effect of MDC-22 in preclinical models of pancreatic cancer. In the present work, we examined the therapeutic effects of MDC-22 in patient-derived tumor xenografts (PDTXs) and in LSL-Kras^G12D/+, LSL-Trp53^R172H/+, Pdx1-Cre (KPC) genetically engineered mice, two complementary and clinically relevant animal models of pancreatic cancer. In addition, we evaluated whether MDC-22 could synergize with current chemotherapeutic drugs used in the clinic. MDC-22 reduced the growth of various human pancreatic cancer cell lines in a concentration-dependent manner. In vivo, MDC-22 strongly reduced patient-derived pancreatic tumor xenograft growth by 50%, and extended survival of LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx1-Cre (KPC) mice by over a month (5.3 months versus 7.0 months). In both models, MDC-22 inhibited EGFR activation and its downstream signals, including ERK and FAK phosphorylation. In human pancreatic cancer cell lines, MDC-22 enhanced the growth inhibitory effect of irinotecan, and to a lesser degree those of gemcitabine and nab-paclitaxel. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of, both, MDC-22 alone or in combination with irinotecan, indicating selectivity. Furthermore, MDC-22 enhanced irinotecan''s effect on cell migration, in part, by inhibiting EGFR/FAK signaling. Collectively, our results indicate that MDC-22 is an effective anticancer drug in preclinical models of pancreatic cancer, and suggest that MDC-22 plus irinotecan as drug combination strategy for pancreatic cancer treatment, which warrants further evaluation.     

Bone conductive implantation in asymmetric hearing loss (AHL)

Abstract

Background: Bone conductive implants (BCI) represent one possible solution for rehabilitation of single-sided deafness (SSD).

Aims: The aim of the present study was to verify the efficacy of bone conduction implantation in subjects with unilateral severe-to-profound hearing loss and contralaterally impaired hearing, that is, asymmetric hearing loss (AHL), and to compare it with known BCI indications for SSD.

Material and methods: Twenty-one subjects received BCI for either SSD or AHL. All of the subjects underwent a battery of audiological and subjective tests, Data were collected and statistically evaluated within and between the SSD group and the AHL group.

Results: A PTA threshold gain was observed in AHL patients along with improved values in speech audiometry in quiet and noise. The two visual analogue scale evaluations (QoL and QoS) and the GBI showed significantly better scores in AHL patients compared to SSD patients.

Conclusions: BCI provided improvement for auditory or speech recognition in AHL subjects, as compare to SSD. From these findings, it is possible to predict a positive role of BCI for some audiological aspects of AHL subjects that are generally not present or not detectable in SSD cases.