Novel HIV‐1 clade B candidate vaccines designed for HLA‐B*5101+ patients protected mice against chimaeric ecotropic HIV‐1 challenge

Novel candidate HIV‐1 vaccines have been constructed, which are tailor‐designed for HLA‐B^*5101⁺ patients infected with HIV‐1 clade B. These vaccines employ novel immunogen HIVB‐B^*5101 derived from consensus HIV‐1 clade B Gag p17 and p24 regions coupled to two Pol‐derived B^*5101‐restricted epitopes, which are together with a third B^*5101 epitope in Gag dominant in HIV‐1‐infected long‐term non‐progressing patients. Both plasmid DNA and modified vaccinia virus Ankara (MVA) vectors supported high expression levels of the HIVB‐B^*5101 immunogen in cultured cells. Heterologous DNA prime‐recombinant MVA boost regimen induced efficiently HIV‐1‐specific CD8⁺ T‐cell responses in BALB/c mice. These vaccine‐elicited T cells were multifunctional, killed efficiently target cells in vivo, and protected mice against challenge with ecotropic HIV‐1/NL4‐3 and ecotropic HIV‐1/NDK chimaeric viruses with HIV‐1 clade B or D backbones, respectively, and ecotropic murine leukemia virus gp80 envelope, and therefore did so in the absence of anti‐HIV‐1 gp120 antibodies. These results support further development of HIVB‐B^*5101 vaccines in combined heterologous‐modality regimens. The use of allele‐specific vaccines in humans is discussed in the context of other developments in the HIV‐1 field.     

Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan‐induced toxicity in Asian cancer patients: Meta‐analysis

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecan‐induced severe toxicities in Asian cancer patients are inconclusive. Also, ABCC2 c.3972C>T may affect toxicity of irinotecan. The aim was to assess the aggregated risk of neutropenia or diarrhea in Asian cancer patients taking irinotecan and inherited UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic variants. A PubMed literature search for eligible studies was conducted. Odds ratios (ORs) were measured using RevMan software where p values <0.05 were statistically significant. Patients that inherited both UGT1A1*6 and UGT1A1*28 genetic variants (heterozygous: UGT1A1*1/*6 + *1/*28 and homozygous: UGT1A1*6/*6 + *28/*28) were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1 (neutropenia: OR 2.89; 95% CI 1.97–4.23; p < 0.00001; diarrhea: OR 2.26; 95% CI 1.71–2.99; p < 0.00001). Patients carrying homozygous variants had much stronger effects in developing toxicities (neutropenia: OR 6.23; 95% CI 3.11–12.47; p < 0.00001; diarrhea: OR 3.21; 95% CI 2.13–4.85; p < 0.00001) than those with heterozygous variants. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98–2.84; p = 0.06) and were significantly associated with a reduction in irinotecan‐induced diarrhea (OR 0.31; 95% CI 0.11–0.81; p = 0.02). Asian cancer patients should undergo screening for both UGT1A1*6 and UGT1A1*28 genetic variants to reduce substantially irinotecan‐induced severe toxicities.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cancer patients taking irinotecan and inheriting either UGT1A1*6 or UGT1A1*28 genetic polymorphisms or a combination of these variants (UGT1A1*6 + UGT1A1*28) are associated with severe toxicities such as neutropenia or diarrhea, but the aggregated risk is highly inconsistent, especially in Asian cancer patients. Also, the ABCC2 c.3972C>T genetic polymorphism is associated with irinotecan‐induced toxicities.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Is the combination of UGT1A1*6 and UGT1A1*28 genetic polymorphisms or ABCC2 c.3972C>T genetic variant associated with severe neutropenia or diarrhea in Asian cancer patients?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Asian cancer patients, irrespective of the type of cancer, who carried both the UGT1A1*6 and UGT1A1*28 genetic variants were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1, and the effects were even more striking in cancer patients with homozygous variants than those with heterozygous variants. In addition, dose‐dependent analysis indicated that a high dose of irinotecan (>150 mg/m²) was significantly associated with diarrhea in cancer patients that carried both the UGT1A1*6 and UGT1A1*28 genetic variants compared to patients on medium and low doses of irinotecan. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with irinotecan‐induced toxicities.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results presented in this meta‐analysis will greatly enhance the clinical practice of irinotecan therapy considering UGT1A1*6 and UGT1A1*28 pharmacogenetics. The findings of this study will also assist clinicians in suggesting genotyping for UGT1A1*6 and UGT1A1*28 polymorphisms prior to administering irinotecan therapy as part of standard care and may advance the translation of irinotecan pharmacogenetics to the bedside.     

9‐Hydroxyrisperidone‐Induced Hyperprolactinaemia in Thai Children and Adolescents with Autism Spectrum Disorder

Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate the association between plasma drug concentrations of risperidone, 9‐hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorder (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9‐hydroxyrisperidone levels were measured. Patients' clinical data were collected from medical records – age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9‐hydroxyrisperidone level (r_s = 0.355, p < 0.001). The median concentration of 9‐hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86–15.55) was significantly higher than non‐hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10–8.99) after risperidone treatment (p = 0.006). By multivariate analysis, high prolactin level was correlated to high 9‐hydroxyrisperidone level (p = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9‐hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment.     

Ovine atadenovirus,a novel and highly immunogenic vector in prime-boost studies of a candidate HIV-1 vaccine

Ovine adenovirus type 7 (OAdV) is the prototype member of the genus Atadenovirus. No immunity to the virus has so far been detected in human sera. We describe the construction and evaluation of a candidate HIV-1 vaccine based on OAdV and its utilisation alone and in combination with plasmid-, human adenovirus type 5 (HAdV5; a Mastadenovirus)-, and modified vaccinia Ankara (MVA)-vectored vaccines. All vectors expressed HIVA, an immunogen consisting of HIV-1 clade A consensus Gag-derived protein coupled to a T cell polyepitope. OAdV.HIVA was genetically stable, grew well and expressed high levels of protein from the Rous sarcoma virus promoter. OAdV.HIVA was highly immunogenic in mice and efficiently primed and boosted HIV-1-specific T cell responses together with heterologous HIVA-expressing vectors. There were significant differences between OAdV and HAdV5 vectors in priming of naïve CD8⁺ T cell responses to HIVA and in the persistence of MHC class I-restricted epitope presentation in the local draining lymph nodes. OAdV.HIVA primed T cells more rapidly but was less persistent than AdV5.HIVA and thus induced a qualitatively distinct T cell response. Nevertheless, both vectors primed a response in mice that reduced viral titres in a surrogate challenge model by three to four orders of magnitude. Thus, OAdV is a novel, underexplored vaccine vector with potential for further development for HIV-1 and other vaccines. The data are discussed in the context of the latest HIV-1 vaccine developments.     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

T cells induced by recombinant chimpanzee adenovirus alone and in prime‐boost regimens decrease chimeric EcoHIV/NDK challenge virus load

The popularity of nonreplicating adenoviruses of chimpanzee origin (ChAdVs) as vectors for subunit vaccines is on the rise. This is mainly for their excellent safety and impressive immunogenicity observed in human studies to date. Here, we recloned the chimpanzee adenovirus sero type 68 (ChAdV‐68), also designated SAdV‐25 and AdC68, genome and demonstrated its straightforward genetic manipulation facilitated by the use of bacterial artificial chromosome recombineering. To generate the ChAdV68.GagB vaccine, the HIV‐1 consensus clade B Gag‐derived Tg was inserted into the E1 region. In part confirming previous observations, the ChAdV68.GagB vaccine alone and in heterologous prime‐boost regimens with plasmid DNA‐ and modified vaccinia virus Ankara (MVA)‐vectored vaccines induced robust polyfunctional HIV‐1‐specific CD8⁺ and CD4⁺ T‐cell responses with a gut‐homing phenotype. Importantly, we showed that when a single epitope is expressed as an immunodominant CD8⁺ T‐cell determinant, responses elicited by ChAdV68.GagB alone and in combination lowered surrogate challenge EcoHIV/NDK (where EcoHIV is chimeric ecotropic HIV) virus load in mice both at the peak T‐cell frequencies 2 weeks after vaccination and 16 weeks later indicating development of protective effector memory. These results parallel the immunogenicity of similar vaccine regimens in macaques and an ongoing phase I/IIa trial in humans, and support further development of vaccines vectored by ChAdVs.     

Biological Activities of Asparagus Racemosus

Cytotoxic, antioxidant, tyrosinase inhibitory, antimicrobial activities of the crude ethanol extract of dry powdered roots of Asparagus racemosus (Liliaceae) were investigated. The LC₅₀ to brine shrimp was 2189.49 µg/ml; the EC₅₀ for DPPH radical scavenging was 381.91 µg/ml; the IC₅₀ for tyrosinase inhibition was 7.98 mg/ml. The extract was active at 5–20 mg/ml against various pathogenic microbial (16 species, 18 strains) using the agar dilution assay, with the minimum inhibitory concentration (MIC) between 10–20 mg/ml for enteropathogens, the MIC between 5–20 mg/ml for dermatopathogens, and MIC = 10 mg/ml for a pneumonia causing bacteria Klebsiella pneumoniae. TLC and HPLC finger printing showed the presence of steroids-terpenes, alkaloids and flavonoids.     

Biological Activities of Schefflera Leucantha

This study investigated various biological activities of the ethanolic extract of dried ground leaves of Schefflera leucantha Viguier (Araliaceae). The extract possessed very low cytotoxicity to brine-shrimp with the LC₅₀ of 4,111.15µg/ml; the significant antioxidant activity on DPPH with the EC₅₀ of 71.90µg/ml; the inhibitory activity on mushroom tyrosinase with the IC₅₀ of 10.53mg/ml using the dopachrome microplate-assay. The extract of 5–20mg/ml range in the agar dilution assay were active against various pathogenic microbial (11 species, 11 strains), with the minimum inhibitory concentration (MIC) of 5mg/ml against Clostridium spp.; MIC=10mg/ml against enteropathogens as Bacteroides spp., Enterococcus faecalis ATCC 29212, Lactobacillus spp., Peptococcus spp. and Streptococcus mutans; MIC=10mg/ml against a pneumonia causing bacteria Klebsiella pneumoniae and a dermatopathogen as Propionibacterium acnes; MIC=20mg/ml against dermatopathogens as Staphylococcus aureus ATCC 6538, Streptococcus spp. and Candida albicans ATCC 90028. TLC fingerprints of the specific extracts from the leaf powder exhibited zones of steroids-terpenes and flavonoids. HPLC fingerprint of the flavonoid extract was performed.     

The impact of shareholding networks for facilitating care in rural Thailand

This study explored the existential meaning of being a participant in shareholding networks for the care of older people in Thailand. Ten older persons were interviewed about their experiences of participating in the networks. A reflective lifeworld perspective based on phenomenological philosophy was used. The findings show that participating in shareholding network activities entails an always-present existence of aging intertwined with life. Its constituents further describe the essential meaning of the phenomenon: “experience of improved self-management”, “feeling of increased self-esteem”, and “bridging a gap in the care of older people”. Participation in shareholding network activities means keeping contact with oneself and being able to have a life that corresponds to how one perceives oneself to be and must therefore be understood from a holistic perspective. The present study recommends that older persons’ need for support include places where safe and profound reflection on existential issues.