Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Introduction: Collaborative interactions between several diverse biological processes govern the onset and progression of breast cancer. These processes include alterations in cellular metabolism, anti-tumor immune responses, DNA damage repair, proliferation, anti-apoptotic signals, autophagy, epithelial-mesenchymal transition, components of the non-coding genome or onco-mIRs, cancer stem cells and cellular invasiveness. The last two decades have revealed that each of these processes are also directly regulated by a component of the cell cycle apparatus, cyclin D1.

Area covered: The current review is provided to update recent developments in the clinical application of cyclin/CDK inhibitors to breast cancer with a focus on the anti-tumor immune response.

Expert opinion: The cyclin D1 gene encodes the regulatory subunit of a proline-directed serine-threonine kinase that phosphorylates several substrates. CDKs possess phosphorylation site selectivity, with the phosphate-acceptor residue preceding a proline. Several important proteins are substrates including all three retinoblastoma proteins, NRF1, GCN5, and FOXM1. Over 280 cyclin D3/CDK6 substrates have b\een identified. Given the diversity of substrates for cyclin/CDKs, and the altered thresholds for substrate phosphorylation that occurs during the cell cycle, it is exciting that small molecular inhibitors targeting cyclin D/CDK activity have encouraging results in specific tumors.     

A basal‐enriched microRNA is required for prostate tumorigenesis in a Pten knockout mouse model

MicroRNAs (miRNAs) play important roles in prostate cancer development. However, it remains unclear how individual miRNAs contribute to the initiation and progression of prostate cancer. Here we show that a basal layer‐enriched miRNA is required for prostate tumorigenesis. We identify miR‐205 as the most highly expressed miRNA and enriched in the basal cells of the prostate. Although miR‐205 is not required for normal prostate development and homeostasis, genetic deletion of miR‐205 in a Pten null tumor model significantly compromises tumor progression and does not promote metastasis. In Pten null basal cells, loss of miR‐205 attenuates pAkt levels and promotes cellular senescence. Furthermore, although overexpression of miR‐205 in prostate cancer cells with luminal phenotypes inhibits cell growth in both human and mouse, miR‐205 has a minimal effect on the growth of a normal human prostate cell line. Taken together, we have provided genetic evidence for a requirement of miR‐205 in the progression of Pten null‐induced prostate cancer.     

Plasmacytic cutaneous pathology: A review

We review the spectrum of cutaneous disorders associated with inflammatory and neoplastic plasmacytic pathology. Because plasma cells are derived from B‐lymphocytes our overview includes discussion of certain lymphoplasmacytic proliferations. It is structured along histopathological lines, addressing conditions characterized by (a) cutaneous plasma cell infiltrates, (b) deposits of plasma cell products or their derivatives in the skin and (c) miscellaneous, poorly understood cutaneous complications of plasmacytic disorders. Lesions arising primarily in the skin and those due to cutaneous involvement by multisystem disorders are addressed. The range includes a spectrum of tumefactive and circulatory manifestations. We highlight key clinical and pathological features of the different conditions and outline recent advances in our understanding of these entities. By emphasizing the dermatopathological characteristics of this spectrum of disorders we hope to hone the diagnostic accuracy of practitioners in the field.     

Prosthetic treatment in the adult French population: Prevalence and relation with demographic,socioeconomic and medical characteristics

BackgroundThe aim of this study was to estimate the prevalence of dental prosthetic treatment and to investigate the demographic, social, economic and medical factors associated with the use of fixed and removable dentures in a representative sample of adults living in France.MethodsThe data were obtained from the 2002–2003 Decennial Health Survey, a cross-sectional study of a representative sample of the population living in France, which included 29,679 adults. Information was collected by interview. The variables collected were fixed denture, removable denture, age, gender, number of children, area of residence, nationality, educational attainment, family social status, employment status, annual household income per capita, supplementary insurance, chronic disease, eyesight problems/glasses, hearing problems/hearing aids. Multinomial logistic regression models were used to study the relationship between prosthetic treatment and demographic, socioeconomic and medical characteristics unadjusted, adjusted for age and adjusted for all the characteristics.ResultsThe prevalence of prosthetic treatment was 34.6% (95% confidence interval (CI): [34.1; 35.2]) for fixed prosthetic dentures and 13.8% (95% CI: [13.4; 14.2]) for removable prosthetic dentures. We showed a gradient between educational attainment and removable dentures; the odds ratio adjusted for all the variables (aOR) associated with no or primary education compared to post-secondary education was 2.56; 95% CI: [2.09; 3.13]. When annual household income per capita was low, subjects were less likely to report fixed dentures (aOR = 0.68; 95% CI: [0.62; 0.75]) than those with high annual household income per capita. Individuals without insurance less often reported fixed dentures than those with private insurance. Those reporting chronic disease were less likely to report fixed dentures (aOR = 0.87; 95% CI: [0.79; 0.95]) but more likely to report removable dentures (aOR = 1.29; 95% CI: [1.17; 1.43]) than those without chronic disease.ConclusionThis study reveals social, economic and medical inequalities in fixed and removable prosthetic treatment among adults in France.     

Effects of age,gender and menstrual cycle on platelet function assessed by impedance aggregometry

Platelets are needed to prevent or arrest bleeding and aggregate at the site of injury upon vascular damage. Platelets express receptors for estrogens which might affect the function of the platelets and their hemostatic ability. The aim was to identify possible differences in platelet function related to age, gender, and phases of the menstrual cycle by use of impedance aggregometry with Multiplate. In the first part of the study, platelet function was assessed in 60 healthy individuals (30 men and 30 women) in each of three age groups (20–25, 40–45, and 60–65 years). In the second part of the study, the platelet function was analyzed on four occasions during the menstrual cycle in women without oral contraceptives (OCs) (n = 17) and compared to 19 women on OCs and 18 men of similar age (20–40 years). For the women on OCs, aggregation was analyzed once during the tablet-free week and once late during the period with OCs. The men were sampled once. Women of younger age (<45 years) had significantly higher agonist-induced aggregation response than both men and post-menopausal women (60–65 years). The agonist-induced aggregation response did not differ between phases of the menstrual cycle or OC use. The results suggest that estradiol and/or progesterone affect spontaneous aggregation since it was found to be lowest in the mid-luteal phase. Spontaneous aggregation was significantly lower in women on OCs than in both men and women without OCs. Our findings indicate that fertile age is associated with higher aggregation response capacity of the platelets, possibly to prevent excessive bleeding during menstruation, but this response capacity is not altered during the menstrual cycle or by use of OCs.