Publications

The first studies of epidermal growth factor receptor (EGFR) inhibitors in metastatic colorectal cancer were begun before the predictive role of RAS mutations had been elucidated. Secondary analyses of many large randomized trials have shown that mutations in exons 2-4 of KRAS and NRAS, BRAF V600E mutation, and right-sided primary tumor all predict lack of response to EGFR inhibition in the first-line setting. However, even in patient populations defined by a lack of these negative predictors, there is still not uniform response to anti-EGFR therapy. Additionally, although older adults have been shown to have the potential to both tolerate and respond to anti-EGFR therapy, the criteria for selecting the most appropriate older patients for treatment remain unclear.

Background

In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria.

Methods

We compared genotypes using sequencing, fluorescent microsphere, and quantitative polymerase chain reaction assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP.

Results

Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, P < .001; 93.9% vs 59.2%, P < .001; and 87.7% vs 75.4%, P = .03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/mL. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5-mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, P = .001).

Conclusions

IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.

Tissue-resident memory (T) CD8 T-cells are non-recirculating, long-lived cells housed in tissues that can confer protection against mucosal pathogens. Human immunodeficiency virus-1 (HIV-1) is a mucosal pathogen and the gastrointestinal tract is an important site of viral pathogenesis and transmission. Thus, CD8 T cells may be an important effector subset for controlling HIV-1 in mucosal tissues. This study sought to determine the abundance, phenotype, and functionality of CD8 T cells in the context of chronic HIV-1 infection. We found that the majority of rectosigmoid CD8 T-cells were CD69CD103S1PR1 and T-betEomesodermin, indicative of a tissue-residency phenotype similar to that described in murine models. HIV-1-specific CD8 T responses appeared strongest in individuals naturally controlling HIV-1 infection. Two CD8 T subsets, distinguished by CD103 expression intensity, were identified. CD103 CD8 T primarily displayed a transitional memory phenotype and contained HIV-1-specific cells and cells expressing high levels of Eomesodermin, whereas CD103 CD8 T primarily displayed an effector memory phenotype and were Eomesodermin. These findings suggest a large fraction of CD8 T-cells housed in the human rectosigmoid mucosa are tissue-resident and that T contribute to the anti-HIV-1 immune response. Further exploration of CD8 T will inform development of anti-HIV-1 immune-based therapies and vaccines targeted to the mucosa.