The oncogenic lncRNA MIR503HG suppresses cellular senescence counteracting supraphysiological androgen treatment in prostate cancer.

Background: The androgen receptor (AR), a ligand-dependent transcription factor, plays a key role in regulating prostate cancer (PCa) growth. The novel bipolar androgen therapy (BAT) uses supraphysiological androgen levels (SAL) that suppresses growth of PCa cells and induces cellular senescence functioning as a tumor suppressive mechanism. The role of long non-coding RNAs (lncRNAs) in the regulation of SAL-mediated senescence remains unclear.

Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence.

Background: Prostate cancer (PCa) is a public health problem mostly reported in developed countries. The androgen receptor (AR) regulates the development and physiological function of normal prostate as well as the proliferation of cancerous prostate tissue. Treatment with supraphysiological androgen levels (SAL) is used in bipolar androgen therapy and inhibits PCa growth, suggesting SAL induces a tumor suppressive program.

Plasmodium falciparum African PfCRT Mutant Isoforms Conducive to Piperaquine Resistance are Infrequent and Impart a Major Fitness Cost.

Background: Piperaquine, used in combination with dihydroartemisinin, has been identified as a promising partner drug for uncomplicated treatment and chemoprevention of Plasmodium falciparum malaria in Africa. In light of the earlier spread of piperaquine resistance in Southeast Asia, mediated primarily by mutations in the drug efflux transporter PfCRT, we have explored whether PfCRT mutations would represent a probable path to piperaquine resistance becoming established in Africa.

Methods: We edited PfCRT mutations known to mediate piperaquine resistance in Southeast Asia into P.

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.