Mechanochemical Synthesis and Molecular Docking Studies of New Azines Bearing Indole as Anticancer Agents.

The development of new approaches for the synthesis of new bioactive heterocyclic derivatives is of the utmost importance for pharmaceutical industry. In this regard, the present study reports the green synthesis of new benzaldazine and ketazine derivatives via the condensation of various carbonyl compounds (aldehydes and ketones with the 3-(1-hydrazineylideneethyl)-1H-indole using the grinding method with one drop of acetic acid). Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. Furthermore, the anticancer activities of the reported azine derivatives were evaluated against colon, hepatocellular, and breast carcinoma cell lines using the MTT technique with doxorubicin as a reference medication. The findings suggested that the synthesized derivatives exhibited potential anti-tumor activities toward different cell lines. For example, 3c, 3d, 3h, 9, and 13 exhibited interesting activity with an IC50 value of 4.27-8.15 µM towards the HCT-116 cell line as compared to doxorubicin (IC50 = 5.23 ± 0.29 µM). In addition, 3c, 3d, 3h, 9, 11, and 13 showed excellent cytotoxic activities (IC50 = 4.09-9.05 µM) towards the HePG-2 cell line compared to doxorubicin (IC50 = 4.50 ± 0.20 µM), and 3d, 3h, 9, and 13 demonstrated high potency (IC50 = 6.19-8.39 µM) towards the breast cell line (MCF-7) as compared to the reference drug (IC50 = 4.17 ± 0.20 µM). The molecular interactions between derivatives 3a-h, 7, 9, 11, 13, and the CDK-5 enzyme (PDB ID: 3IG7) were studied further using molecular docking indicating a high level of support for the experimental results. Furthermore, the drug-likeness analysis of the reported derivatives indicated that derivative 9 (binding affinity = -8.34 kcal/mol) would have a better pharmacokinetics, drug-likeness, and oral bioavailability as compared to doxorubicin (-7.04 kcal/mol). These results along with the structure-activity relationship (SAR) of the reported derivatives will pave the way for the design of additional azines bearing indole with potential anticancer activities.

Norovirus vaccine against experimental human GII.4 virus illness: a challenge study in healthy adults.

BACKGROUND: Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission. METHODS: In this randomized, double-blind, placebo-controlled trial, 18- to 50-year-olds received 2 injections of placebo or norovirus GI.1/GII.4 bivalent vaccine-like particle (VLP) vaccine with 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and alum. Participants were challenged as inpatients with GII.4 virus (4400 reverse transcription polymerase chain reaction [RT-PCR] units), and monitored for illness and infection. RESULTS: Per protocol, 27 of 50 (54.0%) vaccinees and 30 of 48 (62.5%) controls were infected. Using predefined illness and infection definitions, vaccination did not meet the primary endpoint, but self-reported cases of severe (0% vaccinees vs. 8.3% controls; P = .054), moderate or greater (6.0% vs. 18.8%; P = .068), and mild or greater severity of vomiting and/or diarrhea (20.0% vs. 37.5%; P = .074) were less frequent. Vaccination also reduced the modified Vesikari score from 7.3 to 4.5 (P = .002). Difficulties encountered were low norovirus disease rate, and inability to define illness by quantitative RT-PCR or further antibody rise in vaccinees due to high vaccine-induced titers. By day 10, 11 of 49 (22.4%) vaccinees were shedding virus compared with 17 of 47 (36.2%) placebo recipients (P = .179). CONCLUSIONS: Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration. NCT01609257.

Norovirus vaccine against experimental human Norwalk Virus illness.

BACKGROUND: Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. RESULTS: Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus-specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05). CONCLUSIONS: This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284.).

Nano Iron Versus Bulk Iron Forms as Functional Feed Additives: Growth, Body Indices, Hematological Assay, Plasma Metabolites, Immune, Anti-oxidative Ability, and Intestinal Morphometric Measurements of Nile tilapia, Oreochromis niloticus.

The current study aimed to compare the utilization efficiency of iron (Fe) feed additives from either bulk or nano sources in Nile tilapia, Oreochromis niloticus diets on growth, haematological, immunity, anti-oxidative, and intestinal topography capacities. Five isonitrogenous and isoenergetic diets were performed; the basal diet served as a control with no Fe added, whereas the experimental diets were shaped by adding bulk-Fe2O3 and nano-Fe2O3 to the basal diet to preserve Fe levels at 0.2 and 0.4 mg kg-1, respectively. Results indicated that superior growth performance was recorded in fish-fed diets supplemented with 0.4 nano-Fe2O3 mg kg-1 diet. In addition, the highest (P ≤ 0.05) survival rate, absorption area of villous (AAV), mucosal to serosal amplification ratio (MSR), and villi parameters (height and width) were noticed in fish fed diet enrichment with either bulk or nano-Fe2O3 source. However, the superiority observed in nano-Fe2O3 fish groups. Also, the highest values of plasma albumin, total protein, high-density lipoprotein cholesterol (HDL-C), white blood cells (WBCs), and lymphocyte absolute count (LYM) (P ≤ 0.05) recorded in fish fed a diet supplemented with nano-Fe2O3 versus the basal diet. Moreover, the highest values of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and plasma lysozyme activity (P ≤ 0.05) were observed in fish fed 0.4 mg/kg-1 nano-Fe2O3, while the lowest value was recorded in fish fed the control diet. The best value of malondialdehyde activity (P ≤ 0.05) recorded in a fish-fed diet supplemented with 0.4 mg/kg-1 nano-Fe2O3. The current findings emphasize the importance of including Fe to improve fish growth, immunity, antioxidant capabilities, and intestinal structure, primarily with a nano-Fe source, which demonstrated a more effective function in satisfying Nile tilapia dietary Fe requirements and improving the aforementioned parameters.

Interaction of antitumor flavonoids with dsDNA in the absence and presence of Cu(II).

The binding of antitumor flavonoids, namely 3-hydroxyflavone (3HF) and hesperidin (Hesp) with dsDNA was investigated in the absence and presence of Cu(II) using cyclic voltammetry and square wave voltammetry at the hanging mercury drop electrode. The reduction currents of 3HF, 3HF-Cu complex, and the 3HF-ß-cyclodextrin inclusion complex decreased after intercalation into dsDNA. The intercalation of Hesp into dsDNA is weak. dsDNA is reduced at a potential of -1.48 V overlaying the reduction of Hesp. In contrast, in the presence of Cu(II), the interaction of Hesp with dsDNA leads to a much stronger intercalation. The binding constants of the flavonoid-Cu complex with dsDNA were evaluated and calibration graphs for the determination of dsDNA were obtained from the decrease in the peak current in the cyclic voltammograms of 3HF in the presence of dsDNA. The proposed method exhibited good recovery and reproducibility for indirect determination of dsDNA.

Novel maleic anhydride derivatives: liquid crystalline materials with enhanced mesomorphic and optical characteristics.

A new class of liquid crystalline materials, 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl 4-(alkoxy)benzoates (Mn), derived from maleic anhydride, was synthesized and studied for mesomorphic and optical properties. These materials consist of three derivatives with varying terminal flexible chain lengths (6-12 carbons) linked to the phenyl ring near the ester bond. The study employed differential scanning calorimetry and polarized optical microscopy (POM) to characterize the mesomorphic properties. Molecular structures were elucidated using elemental analysis, FT-IR, and NMR spectroscopy. The findings reveal that all the synthesized maleic anhydride derivatives exhibit enantiotropic nematic (N) mesophases. The insertion of the heterocyclic maleic anhydride moiety into the molecular structure influences the stability and range of the N phase. Additionally, entropy changes during N-isotropic transitions are of small magnitude and exhibit non-linear trends independent of the terminal alkoxy chain length (n). This suggests that the ester linkage group does not significantly promote molecular biaxiality, and the clearing temperature values are relatively high. By comparing the investigated materials with their furan derivatives found in existing literature, it was established that the substitution examined in this study induces the formation of nematic phases.

Evaluation of Different Copper Sources in Nile Tilapia Diets: Growth, Body Indices, Hematological Assay, Plasma Metabolites, Immune, Anti-Oxidative Ability, and Intestinal Morphometric Measurements.

The goal of the current study was to compare how well Nile tilapia, Oreochromis niloticus, utilized copper (Cu) as bulk and nano sources by evaluating fish growth, body indices, hematological assays, plasma metabolites, immune and anti-oxidative abilities, and intestinal morphometric measurements. The basal diet served as a control, with no Cu added, whereas the experimental diets were formed by adding bulk-Cu and nano-Cu to the basal diet to keep Cu levels at 3 and 6 mg kg-1, respectively, in both Cu sources. Tilapia (9.10 ± 0.014 g) were fed the control diet and four experimental diets for 12 weeks. Results indicated that growth, feed utilization, and body indices demonstrated a substantial improvement (P ≤ 0.05) in tilapia that received a diet containing 3 and 6 Nano-Cu mg kg-1 diet, compared to the performance of fish that received diets containing 3 and 6 Bulk-Cu mg kg-1 diet and the control diet. Villi height, villi width, absorption area of villous (AAV), and mucosal to serosal amplification ratio (MSR) values demonstrated a substantial increase (P ≤ 0.05) in tilapia fed 3 and 6 mg kg-1 Nano-Cu compared to the values observed in fish fed the control and Bulk-Cu supplemented diets. Fish fed Bulk-Cu recorded the highest (P ≤ 0.05) hemoglobin concentration in those fed 6 mg kg-1 compared to 3 mg kg-1. Hematocrit value considerably improved (P ≤ 0.05) by supplementation of Cu, whereas the highest significant value demonstrated in fish provided 6 mg/kg-1 Nano-Cu. A fish-fed diet containing 3 mg kg-1 Nano-Cu revealed the best (P ≤ 0.05) values of plasma albumin, total protein, and globulins. Plasma HDL-C highest concentrations (P ≤ 0.05) were reported in fish fed diet supplemented with 6 mg/kg-1 either Bulk or Nano Cu, whereas values of plasma TG and VLDL-C declined as Cu supplementation level increased either from Bulk or Nano source. Also, the best (P ≤ 0.05) values of CAT and GPX were seen in fish given diet supplemented with 6 Nano-Cu mg/kg-1. Fillets of fish-fed Nano-Cu-supplemented diets showed a marked decline (P ≤ 0.05) in moisture and fat contents, while crude protein, ash, and Cu contents considerably increased in the fillet by dietary supplementation of Nano-Cu at both levels 3 and 6 mg kg-1. In conclusion, the supplemental diets with 3 or 6 Nano-Cu mg/kg-1 enhanced growth, feed utilization, body indices, fillet nutrient composition, hematological assay, plasma metabolites, immune, antioxidant activities, and intestinal morphometry of Nile tilapia.

Synthesis, Biological Evaluation, and Molecular Docking of Novel Azolylhydrazonothiazoles as Potential Anticancer Agents.

A novel set of thiazolylhydrazonothiazoles bearing an indole moiety were synthesized by subjection reactions of carbothioamide derivative and hydrazonoyl chlorides (or α-haloketones). The cytotoxicity of the synthesized compounds was evaluated against the colon carcinoma cell line (HCT-116), liver carcinoma cell line (HepG2), and breast carcinoma cell line (MDA-MB-231), and demonstrated encouraging activity. Furthermore, when representative products were assessed for toxicity against normal cells, minimal toxic effects were observed, indicating their potential safety for use in pharmacological studies. The mechanism of action of the tested products, as inhibitors of the epidermal growth factor receptor tyrosine kinase domain (EGFR TK) protein, was suggested through docking studies that assessed their binding scores and modes, in comparison to a reference standard (W19), thus endorsing their anticancer activity.

Erratum: Correction of missing funding information. A new phantom to evaluate the tissue dissolution ability of endodontic irrigants and activating devices.

[This corrects the article e45 in vol. 45, PMID: 33294410.].

Nano Zinc Versus Bulk Zinc Form as Dietary Supplied: Effects on Growth, Intestinal Enzymes and Topography, and Hemato-biochemical and Oxidative Stress Biomarker in Nile Tilapia (Oreochromis niloticus Linnaeus, 1758).

Five isonitrogenous diets were formulated to comprise two forms of zinc (Zn): convention zinc oxide named Bulk-ZnO or zinc oxide nanoparticles (Nano-ZnO) supplemented at two levels 30 and 60 mg kg-1 compared to the control diet. Nile tilapia, Oreochromis niloticus, fingerlings (5.02-5.05 g) were fed tested diets two times a day for 84 days. The results displayed that the best growth and digestive enzyme activity (P < 0.05) were noticed in fish fed 60 mg kg-1 Nano-ZnO. Moreover, significant (P < 0.05) improvement in intestinal topography was observed in 60 mg kg-1 Nano-ZnO group versus other treatments. Furthermore, fish fed 30 mg kg-1 Nano-ZnO recorded the best values of hematological indices (P < 0.05). The alanine and aspartate aminotransferase (ALT and AST) values were lower, while total serum protein, albumin, and globulin contents were clearly higher in fish fed diet that contained 30 mg kg-1 Nano-ZnO versus other groups. The significant highest values of oxidative enzyme activity escorted with lower malondialdehyde value recorded of fish fed diet supplemented with 60 mg kg-1 Nano-ZnO. The results indicated that inclusion of Nano-ZnO at 60 mg kg-1 was the recommended source to enhance growth, feed utilization, amylase and lipase enzymes activity, intestinal morphology, hemato-biochemical, and oxidative response biomarkers of Nile tilapia compared with Bulk-ZnO in commercial tilapia feeds.

Is 9-field IMRT superior to 7-field IMRT in the treatment of nasopharyngeal carcinoma?

BACKGROUND: To evaluate the pros and cons of 9-field intensity modulated radiotherapy (IMRT) compared to 7-field IMRT in the treatment of nasopharyngeal carcinoma (NPC). METHODS: Ten NPC patients were treated with 7F-IMRT and 9F-IMRT. A dose prescription of 70 Gy was delivered in 35 fractions to gross planning target volume (PTV1). Plan verification was performed via 2D-array and film dosimetry. Dose-Volume Histogram (DVH) parameters were used to evaluate the quality of IMRT plans. RESULTS: Dose data for the investigated planning techniques obeyed the Radiation Therapy Oncology Group (RTOG) protocol no. 0615. The dose delivered to PTV1 and organs-at-risk (OARs) for 9F-IMRT was significantly better than 7F-IMRT, except for OARs which were at a distance from PTV1, such as eyes, optical nerves, and chiasma. Ninety five percent of PTV1 was covered by more than 95% of the prescribed dose (67.75 ± 1.1 Gy and 68.57 ± 1.2 Gy for 7F-IMRT and 9F-IMRT, respectively). The maximum dose to 1% of brainstem was 50.06 ± 2.7 Gy and 47.75 ± 2.6 Gy for 7F-IMRT and 9F-IMRT, respectively. Dose verification showed good agreement with treatment planning system with a maximum deviation for 2D-array of 2.16% ± 0.86 and 1.73% ± 0.33 for 7F-IMRT and 9F-IMRT, respectively. Similarly, radiochromic film reported maximum dose deviations of 3.38% ± 1.68 and 2.77% ± 1.3, respectively. CONCLUSION: 9F-IMRT provides better homogenous dose to PTV1 and more sparing of OARs over 7F-IMRT for NPC patients, except for OARs which are are a distance from PTV1.

A new phantom to evaluate the tissue dissolution ability of endodontic irrigants and activating devices.

OBJECTIVE: The aim of this study was to introduce a gelatin/bovine serum albumin (BSA) tissue standard, which provides dissolution properties identical to those of biological tissues. Further, the study evaluated whether the utilization of endodontic activating devices led to enhanced phantom dissolution rates. MATERIALS AND METHODS: Bovine pulp tissue was obtained to determine a benchmark of tissue dissolution. The surface area and mass of samples were held constant while the ratio of gelatin and BSA were varied, ranging from 7.5% to 10% gelatin and 5% BSA. Each sample was placed in an individual test tube that was filled with an appropriate sodium hypochlorite solution for 1, 3, and 5 minutes, and then removed from the solution, blotted dry, and weighed again. The remaining tissue was calculated as the percent of initial tissue to determine the tissue dissolution rate. A radiopaque agent (sodium diatrizoate) and a fluorescent dye (methylene blue) were added to the phantom to allow easy quantification of phantom dissolution in a canal block model when activated using ultrasonic (EndoUltra) or sonic (EndoActivator) energy. RESULTS: The 9% gelatin + 5% BSA phantom showed statistically equivalent dissolution to bovine pulp tissue at all time intervals. Furthermore, the EndoUltra yielded significantly more phantom dissolution in the canal block than the EndoActivator or syringe irrigation. CONCLUSIONS: Our phantom is comparable to biological tissue in terms of tissue dissolution and could be utilized for in vitro tests due to its injectability and detectability.

Larvicidal Activities of Indigenous Bacillus thuringiensis Isolates and Nematode Symbiotic Bacterial Toxins against the Mosquito Vector, Culex pipiens (Diptera: Culicidae).

BACKGROUND: The incidence of mosquito-borne diseases and the resistance of mosquitoes to conventional pesticides have recently caused a panic to the authorities in the endemic countries. This study was conducted to identify native larvicidal biopesticides against Culex pipiens for utilization in the battle against mosquito-borne diseases. METHODS: Larvicidal activities of new indigenous Bacillus thuringiensis isolates and crude toxin complexes (TCs) of two nematode bacterial-symbionts, Photorhabdus luminescens akhurstii (HRM1) and Ph. luminescens akhurstii (HS1) that tested against Cx. pipiens. B. thuringiensis isolates were recovered from different environmental samples in Saudi Arabia, and the entomopathogenic nematodes, Heterorhabditis indica (HRM1) and He. sp (HS1) were isolated from Egypt. Larvicidal activities (LC50 and LC95) of the potentially active B. thuringiensis strains or TCs were then evaluated at 24 and 48h post-treatment. RESULTS: Three B. thuringiensis isolates were almost as active as the reference B. thuringiensis israelensis (Bti-H14), and seven isolates were 1.6-5.4 times more toxic than Bti-H14. On the other hand, the TCs of the bacterial symbionts, HRM1 and HS1, showed promising larvicidal activities. HS1 showed LC50 of 2.54 folds that of HRM1 at 24h post-treatment. Moreover, histopathological examinations of the HS1-treated larvae showed deformations in midgut epithelial cells at 24h post-treatment. CONCLUSION: Synergistic activity and molecular characterization of these potentially active biocontrol agents are currently being investigated. These results may lead to the identification of eco-friend mosquito larvicidal product(s) that could contribute to the battle against mosquito-borne diseases.

Treatment of a Periodontic-Endodontic Lesion in a Patient with Aggressive Periodontitis.

Case Description. This case report describes the successful management of a left mandibular first molar with a combined periodontic-endodontic lesion in a 35-year-old Caucasian woman with aggressive periodontitis using a concerted approach including endodontic treatment, periodontal therapy, and a periodontal regenerative procedure using an enamel matrix derivate. In spite of anticipated poor prognosis, the tooth lesion healed. This case report also discusses the rationale behind different treatment interventions. Practical Implication. Periodontic-endodontic lesions can be successfully treated if dental professionals follow a concerted treatment protocol that integrates endodontic and periodontic specialties. General dentists can be the gatekeepers in managing these cases.

Isolation and characterization of native Bacillus thuringiensis strains from Saudi Arabia with enhanced larvicidal toxicity against the mosquito vector Anopheles gambiae (s.l.).

BACKGROUND: Worldwide, mosquito vectors are transmitting several etiological agents of important human diseases, including malaria, causing millions of deaths every year. In Saudi Arabia, as elsewhere, vector-control is based mostly on chemical insecticides which may be toxic and cause environmental deprivation. Here, to support the development of bio-pesticide alternatives, a study was conducted to identify native Bacillus thuringiensis (Bt) isolates with improved toxicity against the malaria vector, Anopheles gambiae (s.l.). METHODS: Sixty-eight Bt isolates were obtained from 300 soil and other samples collected from 16 sites across Saudi Arabia. Bt identification was based on morphological characteristics of colonies, shape of parasporal crystals and biochemical profiles. After characterization of their mosquitocidal activity, larvicidal strains were described through 16S ribosomal DNA gene sequencing, cry, cyt and chi genes PCR-amplification profiles, and SDS-PAGE protein analyses. RESULTS: Spherical Bt crystals were predominant amongst the 68 isolates (34%), while irregular, bi-pyramidal and spore-attached crystals were found in 32, 13 and 21% of strains, respectively. LC50 and LC90 bioassays showed that 23/68 isolates were larvicidal, with distinct biochemical activity profiles compared to non-larvicidal Bt strains. Eight larvicidal strains showed larvicidal activity up to 3.4-fold higher (LC50 range: 3.90-7.40 µg/ml) than the reference Bti-H14 strain (LC50 = 13.33 µg/ml). Of these, 6 strains had cry and cyt gene profiles similar to Bti-H14 (cry4Aa, cry4Ba, cry10, cry11, cyt1Aa, cyt1Ab, cyt2Aa). The seventh strain (Bt63) displaying the highest larvicidal activity (LC50 = 3.90 µg/ml) missed the cry4Aa and cyt1Ab genes and had SDS-PAGE protein profiles and spore/crystal sizes distinct from Bti-H14. The eight strain (Bt55) with LC50 of 4.11µg/ml had cry and cyt gene profiles similar to Bti-H14 but gave a chi gene PCR product size of 2027bp. No strains harbouring cry2, cry17 + 27, cry24 + 40, cry25, cry29, cry30, or cyt2Ba were detected. CONCLUSION: This study represents the first report of several Saudi indigenous Bt strains with significantly higher larvicidal efficacy against An. gambiae than the reference Bti-H14 strain. The very high toxicity of the Bt63 strain, combined with distinct cry and cyt genes and SDS-PAGE-protein profiles makes it a promising candidate for future applications in mosquito bio-control.

Serological Correlates of Protection against a GII.4 Norovirus.

Noroviruses are the leading cause of acute gastroenteritis worldwide, and norovirus vaccine prevention strategies are under evaluation. The immunogenicity of two doses of bivalent genogroup 1 genotype 1 (GI.1)/GII.4 (50 µg of virus-like particles [VLPs] of each strain adjuvanted with aluminum hydroxide and 3-O-desacyl-4'monophosphoryl lipid A [MPL]) norovirus vaccine administered to healthy adults in a phase 1/2 double-blind placebo-controlled trial was determined using virus-specific serum total antibody enzyme-linked immunosorbent assay (ELISA), IgG, IgA, and histoblood group antigen (HBGA)-blocking assays. Trial participants subsequently received an oral live virus challenge with a GII.4 strain, and the vaccine efficacy results were reported previously (D. I. Bernstein et al., J Infect Dis 211:870-878, 2014, doi:10.1093/infdis/jiu497). This report assesses the impact of prechallenge serum antibody levels on infection and illness outcomes. Serum antibody responses were observed in vaccine recipients by all antibody assays, with first-dose seroresponse frequencies ranging from 88 to 100% for the GI.1 antigen and from 69 to 84% for the GII.4 antigen. There was little increase in antibody levels after the second vaccine dose. Among the subjects receiving the placebo, higher prechallenge serum anti-GII.4 HBGA-blocking and IgA antibody levels, but not IgG or total antibody levels, were associated with a lower frequency of virus infection and associated illness. Notably, some placebo subjects without measurable serum antibody levels prechallenge did not become infected after norovirus challenge. In vaccinees, anti-GII.4 HBGA-blocking antibody levels of >1:500 were associated with a lower frequency of moderate-to-severe vomiting or diarrheal illness. In this study, prechallenge serum HBGA antibody titers correlated with protection in subjects receiving the placebo; however, other factors may impact the likelihood of infection and illness after virus exposure. (This study is registered at ClinicalTrials.gov under registration number NCT1609257.).

Implementation of a wedged-dynamic arc therapy technique for head and neck cancer.

INTRODUCTION: In this study, we designed and evaluated a wedged dynamic arc therapy (W-DAT) to provide the desirable concaved-shape dose distribution to cover the target in the treatment of head and neck sequence cell carcinoma. MATERIALS AND METHODS: Eight patients were treated using W-DAT. The dose prescriptions were 70 Gy and 54 Gy, in 35 fractions, to the sites of the gross planning target volume (PTV1) and the microscopic (PTV2) diseases respectively. This technique consists of four wedged half-arcs of moving multi-leaf collimator leaves to fit PTV1 and shield brain stem at all gantry rotations. These were combined with two anterior-posterior conformal fields of different weighing to improve the dose uniformity. Another two anterior-posterior conformal fields were designed to cover the PTV2. All of the eight fields were half blocked by the normal jaws so there is no dose overlap at the interface between the two targets. RESULTS: Referring to radiation therapy oncology group protocol 0615, 95% of the PTV1 was covered by more than 95% (66.50 Gy) of the prescribed dose, with very low dose inhomogeneity index of 0.0670 ± 0.0007. The maximum dose to 1% of the planning organ at risk volumes-brainstem didn't exceed 56.10 ± 2.17 Gy while the two parotids were well spared as they received a mean dose of 21.97 ± 3.24 Gy. Isocentric ion chamber measurements showed good agreement with the treatment planning system calculated dose with the maximum deviation of 2.40% while film measurements yielded lesser than 4.20% of the pixels failed the acceptance gamma criteria of (3 mm, 3%). CONCLUSION: W-DAT technique was approved in our department as the standard choice for the radical treatment of head and neck sequence cell carcinoma.

Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin.

BACKGROUND: Development of vaccines against highly pathogenic avian influenza virus H5N1 subtypes posing a pandemic threat remains a priority. Limitations in manufacturing capacity and production time of conventional inactivated vaccines highlight the need for additional approaches. METHODS: We conducted two double-blind, placebo-controlled phase 1 studies involving a total of 103 healthy adults who received two intramuscular injections of Vaxfectin-adjuvanted plasmid DNA vaccine or placebo 21 days apart. Vaccine cohorts received either a monovalent vaccine containing an A/Vietnam/1203/04 H5 hemagglutinin-encoding plasmid or a trivalent vaccine with plasmids encoding H5, NP, and M2 proteins in doses from 0.1 to 1mg of DNA/injection. RESULTS: All doses were well tolerated without vaccine-related serious adverse events or discontinuations. In the monovalent cohorts, hemagglutination inhibition (HI) titers of > or =40 and 4-fold rises from baseline were achieved in 47-67% of subjects and H5-specific T-cell responses in 75-100%. Trivalent cohorts had lower HI response rates (< or = 20%), but 72% of subjects achieved T-cell and/or antibody responses to one or more antigens. CONCLUSIONS: Vaxfectin-adjuvanted monovalent H5 DNA vaccines were well tolerated and induced HI response rates and titers in the reported range of inactivated protein-based H5 vaccines, suggesting that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control.