Background With effective vector control and case management, substantial progress has been made in the elimination of malaria on the islands of São Tomé and Príncipe (STP). During the critical period from the low-transmission to the pre-elimination phase, this study tracked the dynamic changes in the genetic diversity in Plasmodium falciparum, the distribution of antimalarial drug-resistance genes, and the treatment outcomes in patients to provide insights for the prevention of rebounded malaria in STP. Methods Dried blood spots (DBSs) and case follow-up data were collected from malaria patients who had visited the Central Hospital between 2010 and 2016. Genomic DNA of P. falciparum was extracted from DBSs. The polymorphic regions on the genes for merozoite surface proteins 1 and 2 (msp1 and msp2) were amplified in 118 pre-treatment samples to identify the genetic diversity of the infected parasites. Anti-malarial drug resistance mutations in the multi-drug resistance (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (pfK13) genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing in 111 samples. Treatment outcomes were categorized based on the parasitological results from microscopy during the 28-day follow-up after treatment. Factors related to malaria recurrence were characterized by logistic regression models using case follow-up data (total number = 7,482). Results The circulating parasite strains in STP showed significant changes at the recent peak incidence in 2012, during which the prevalent allelic type in MSP1 changed from K1 to MAD20, and that in MSP2 changed from 3D7/IC to FC27. Genotyping results for antimalarial drug-resistance markers showed that the dominant alleles of pfmdr1 86 + 184 + 1246-pfcrt 76 were YFD-T (51.4%). Logistic regression models showed that significant factors related to parasitological failure after treatment were age (protective factor, OR = 0.97–0.98), log10-transformed parasite density (OR = 1.07–1.44), and treatment (quinine vs. artemisinin-based combination therapy, OR = 1.91–1.96). Overall, younger patients, those with higher parasitemia levels at enrollment, and those treated with quinine had a higher risk of recurrence during follow-up. Conclusions Although malaria treatment efficacy remained acceptable in STP, this study showed temporal changes in the dominant strains and the development of drug resistance mutations in the local parasite population. Therapeutic efficacy should be carefully monitored to adequately adjust the policy in the future.
Purpose Deleterious BRCA1 / 2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. PARP (poly ADP ribose polymerase) inhibitors selectively cause failure of single-strand but does not affect double-strand DNA break repair, and ant-tumor activity is observed in BRCA mutant breast cancers. Recently genes implicated into the homologous recombination repair (HRR) pathways are investigated extensively, as defective HRR genes may indicate potential clinical benefits from PARP inhibitors beyond BRCA1 / 2 mutations. Materials and Methods We evaluated the prevalence of BRCA1 / 2 mutations as well as alternations in HRR genes for Taiwanese breast cancers with targeted sequencing. Consecutive 648 breast cancer samples were assayed, and HRR genes by Heeke et al. and those interrogated in Talazoparib Beyond BRCA (TBB) trial were evaluated for prevalence from breast cancer tissues. Results Among 648 breast cancer samples, there were 18 truncating and 2 missense mutations in BRCA1 and 48 truncating and 2 missense mutations in BRCA2 , impacting 3% and 5% of study population (collectively altered in 6%) with co-occurrence of BRCA1 / 2 in 7 breast cancers. On the other hand, HRR genes defined by Heeke et al. were altered in 122 (19%) breast cancers while TBB interrogated genes (excluding BRCA1 / 2 ) were mutated in 107 (17%) patients. Beyond BRCA1/2 , the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%) and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples were impacted by at least one HRR gene. Conclusion The prevalence of high-penetrant BRCA1 / 2 mutations was far below one tenth of assayed samples while the prevalence of tumor DNA mutations in HRR pathways was much higher and approached one fifth among Taiwanese breast cancers. Further studies to evaluate the efficacy of PARP inhibitors in patients with defective HRR gene(s) are warranted to broaden the targeted population of synthetic lethality.
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