Knowledge,Attitudes, and Practices Regarding Cervical Cancer Screening among HIV-infected Women at Srinagarind Hospital: A Cross-Sectional Study

Introduction: In recent years, the lives of HIV-infected patients in Thailand have improved significantly due to continuous advances in treatment. However, the rate of cancer related to HIV infection (especially cervical cancer) is likely to increase. Although the World Health Organization (WHO) recommends Papanicolaou testing in all HIV-infected women, few of these patients receive this kind of screening in Thailand. Therefore, we conducted this study to evaluate the knowledge, attitudes, and practices of these patients with regard to cervical cancer screening. Materials and Methods: This cross-sectional study was conducted in HIV-infected women aged 18-65 years from April to November 2019 via a self-administered cervical cancer screening questionnaire, which consisted of four parts: demographic data, knowledge, attitudes, and practices. Results: Three hundred HIV-infected women were recruited. Most of the participants had good attitudes toward screening and practiced adequate screening (75.3% and 71.3%, respectively). However, only 62 participants (20.7%) demonstrated adequate knowledge. The crucial factors that were associated with adequate screening practice were age 40-49 years-old (AOR =3.26, 95%CI=1.02-10.37), CD4 cell count (AOR = 3.41, 95%CI = 1.29-8.99), having been advised about cervical cancer screening (AOR= 6.23, 95%CI 1.84-21.07), and attitude toward screening (AOR= 5.7, 95%CI = 2.23-14.55). The major reasons for not undergoing screening were embarrassment (41.86%), lack of symptoms (41.86%), fear of the results (36.04%), and fear of pain (36.04%). Conclusion: The reasons for inadequate testing were disregard and misconceptions about the procedure. To prevent invasive cervical lesions in HIV-infected women, health care providers should inform these patients about the importance of regular cervical cancer screening.     

GBT440 increases haemoglobin oxygen affinity,reduces sickling and prolongs RBC half‐life in a murine model of sickle cell disease

A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end‐organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N‐terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half‐life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease‐modifying agent in sickle cell patients.     

The effects of estrone, estradiol and estriol on platelet aggregation induced by adrenaline and adenosine diphosphate

The impact of estrogens on the cardiovascular system and their ability to regulate platelet functions remains controversial. Changes in platelet functions could contribute to thrombotic risk associated with estrogen treatments. Here, we investigated the effects of various forms of estrogen, including estrone (E1), estradiol (E2) and estriol (E3), on platelet aggregation induced by standard agonists (adrenaline and adenosine diphosphate). Platelet-rich plasma (PRP) was prepared from citrated blood donated by 25 normal volunteers. The study on platelet aggregation was carried out in 96-well flat-bottom microtitre plates and assessed using a microplate reader. For studying the effects of each estrogen, PRP was preincubated with 1, 10 and 100 nM of E1, E2 and E3 at 37 degrees C for 20 min, and then coincubated with normal saline (control untreated PRP), adrenaline (ADR) or adenosine diphosphate (ADP) in the microplate. Platelet aggregation was then measured every minute for 8 min. None of the estrogens (E1, E2 and E3) affected platelet aggregation in untreated PRP. Interestingly, only E1 and E3 can synergize the increased platelet aggregation by either ADR or ADP, while the effects of E2 on the increased platelet aggregation by either ADR or ADP depended on internal factors such as endogenous estradiol and platelet aggregated state. Thus, for the rational use of these internal factors for estrogen use, especially E2, in clinical applications, such as hormone replacement therapy, may need evaluation of thrombotic risk.     

Identification of orally active,potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family

We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed against members of PDGFR receptor have been developed through modifications of the novel quinazoline template I. Systematic modifications in the A-bicyclic ring and D-rings of protype I were carried out to afford potent analogues, which display IC(50) values of <250 nM in cellular betaPDGFR phosphorylation assays. An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC(50) values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed. This analogue also inhibits autophosphorylation of Flt-3 ligand-stimulated wild-type Flt-3 and a constitutively activated Flt-3/internal tandem duplication (ITD) with IC(50) values of 30-100 nM. Through this optimization process, 75 was found to be metabolically stable and has desirable pharmacokinetic properties in all animal species studied (F% > 50%, T(1/2) > 8 h). Oral administration of 75 promotes mice survival and significantly delayed disease progression in a Flt-3/ITD-mediated leukemia mouse model and shows efficacy in a nude mouse model of chronic myelomonocytic leukemia.     

Allometric Pharmacokinetic Scaling: Towards the Prediction of Human Oral Pharmacokinetics

Purpose. To evaluate (1) allometric scaling of systemic clearance (CL)using unbound drug concentration, (2) the potential usage of brainweight (BRW) correction in allometric scaling of both CL and oralclearance (CL/F). Methods. Human clearance was predicted allometrically (CLu = a ·W^biv) using unbound plasma concentration for eight Parke-Daviscompounds and 29 drugs from literature sources. When the exponent b_ivwas higher than 0.85, BRW was incorporated into the allometricrelationship (CLu*BRW = a · W^biv). This approach was also applied tothe prediction of CLu/F for 10 Parke-Davis compounds. Human oralt1/2, Cmax, AUC, and bioavailability were estimated based onallometrically predicted pharmacokinetic (PK) parameters. Results. Human CL and CL/F were more accurately estimated usingunbound drug concentration and the prediction was further improvedwhen BRW was incorporated into the allometric relationship. ForParke-Davis compounds, the predicted human CL and CL/F werewithin 50-200% and 50-220% of the actual values, respectively. Theestimated human oral t1/2, Cmax, and AUC were within 82-220%,56-240%, and 73-190% of the actual values for all 7 compounds,suggesting that human oral PK parameters of those drugs could bereasonably predicted from animal data. Conclusions. Results from the retrospective analysis indicate thatallometric scaling of free concentration could be applied to orallyadministered drugs to gain knowledge of drug disposition in man, and to helpdecision-making at early stages of drug development.     

ADAMTSL1 and mandibular prognathism

Mandibular prognathism is characterized by a prognathic or prominent mandible. The objective of this study was to find the gene responsible for mandibular prognathism. Whole exome sequencing analysis of a Thai family (family 1) identified the ADAMTSL1 c.176C>A variant as the potential defect. We cross-checked our exome data of 215 people for rare variants in ADAMTSL1 and found that the c.670C>G variant was associated with mandibular prognathism in families 2 and 4. Mutation analysis of ADAMTSL1 in 79 unrelated patients revealed the c.670C>G variant was also found in family 3. We hypothesize that mutations in ADAMTSL1 cause failure to cleave aggrecan in the condylar cartilage, and that leads to overgrowth of the mandible. Adamtsl1 is strongly expressed in the condensed mesenchymal cells of the mouse condyle, but not at the cartilage of the long bones. This explains why the patients with ADAMTSL1 mutations had abnormal mandibles but normal long bones. This is the first report that mutations in ADAMTSL1 are responsible for the pathogenesis of mandibular prognathism.     

WNT10B mutations associated with isolated dental anomalies

Isolated hypodontia is the most common human malformation. It is caused by heterozygous variants in various genes, with heterozygous WNT10A variants being the most common cause. WNT10A and WNT10B are paralogs that likely evolved from a common ancestral gene after its duplication. Recently, an association of WNT10B variants with oligodontia (severe tooth agenesis) has been reported. We performed mutational analysis in our cohort of 256 unrelated Thai families with various kinds of isolated dental anomalies. In 7 families afflicted with dental anomalies we detected 4 heterozygous missense variants in WNT10B. We performed whole exome sequencing in the patients who had WNT10B mutations and found no mutations in other known hypodontia‐associated genes, including WNT10A, MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, LPR6, TFAP2B, LPR6, NEMO, KRT17, and GREM2. Our findings indicate that the variants c.475G>C [p.(Ala159Pro)], found in 4 families, and c.1052G>A [p.(Arg351His)], found in 1 family, are most probably causative. They also show that WNT10B variants are associated not only with oligodontia and isolated tooth agenesis, but also with microdontia, short tooth roots, dental pulp stones, and taurodontism.     

Genetic characterization of measles viruses that circulated in Thailand from 1998 to 2008

During the period between 1998 and 2008, 48 representative measles viruses (MeVs) circulating in Thailand were subjected to genetic characterization. Three genotypes, G2, D5, and D9 were detected. The results suggested that measles genotype D5, which has been circulating since at least 1998, is the endemic genotype in Thailand. Genotype G2 was detected between 1998 and 2001. In addition, almost all of the MeVs detected throughout the country in 2008 were genotype D9. This is the first report of genotype D9 in Thailand. This report provides important baseline data about measles genotypes in Thailand and this information will be needed to help verify measles elimination in Thailand.