Publications

PURPOSE OF REVIEW

This study aims to describe bone marrow fat changes in diabetes and to discuss the potential role of marrow fat in skeletal fragility.

RECENT FINDINGS

Advances in non-invasive imaging have facilitated marrow fat research in humans. In contrast to animal studies which clearly demonstrate higher levels of marrow fat in diabetes, human studies have shown smaller and less certain differences. Marrow fat has been reported to correlate with A1c, and there may be a distinct marrow lipid saturation profile in diabetes. Greater marrow fat is associated with impaired skeletal health. Marrow fat may be a mediator of skeletal fragility in diabetes. Circulating lipids, growth hormone alterations, visceral adiposity, and hypoleptinemia have been associated with greater marrow fat and may represent potential mechanisms for the putative effects of diabetes on marrow fat, although other factors likely contribute. Additional research is needed to further define the role of marrow fat in diabetic skeletal fragility and to determine whether marrow fat is a therapeutic target.

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggest that miR-383 regulates PCa tumor-initiating/stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor-initiating capacity of CD44+ PCa cells. Also, 'anti-metastatic' effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggest that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.

OBJECTIVE

Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences.

METHODS

Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness.

RESULTS

The prevalence of K65K/K66K in drug-naïve individuals tripled from 11% in 1997 to 37% in 2014 (P < 0.0001, n = 5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14% of the cohort and conferred a fitness advantage in the context of patient-derived multidrug-resistant (MDR) virus in the absence of drug.

CONCLUSION

The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-naïve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.