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.     

Glutamate hypothesis in schizophrenia

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d ‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.     

3D 打印金属假体在关节外科的临床应用

目的总结 3D 打印金属假体在关节外科的应用进展。方法广泛查阅相关文献，总结 3D 打印金属假体治疗关节外科疾病的疗效，包括假体稳定性、术后并发症、骨长入等假体移植中的关键性问题。结果3D 打印金属假体具有良好的匹配度，可精确重建并恢复关节功能，节省手术时间，早中期随访患者满意度较高，在关节外科的应用取得了良好进展。结论3D 打印技术可制造任意形状的个性化微孔结构假体，很好地解决了传统假体存在的特殊患者关节匹配度较差的问题，在骨科领域有巨大应用潜力。     

Vitamin D modulates the allergic phenotype of dendritic cells in children with atopic dermatitis

Vitamin D (VD) deficiency has been associated with increased incidence and severity of atopic dermatitis (AD), but the mechanisms through which VD may ameliorate AD are unclear. We compared the phenotypic characteristics of circulating myeloid and plasmacytoid dendritic cells (mDCs and pDCs, respectively) of children with AD vs healthy controls (HC) and evaluated if VD can modulate the allergic phenotype of circulating DCs in AD patients. Although there was no difference in frequency of circulating DCs between groups, among children with AD there was an inverse correlation between SCORAD and circulating total DCs and mDCs. In AD, serum IgE concentration correlated with FcεRI and surface‐bound IgE expression on mDCs and pDCs; pDCs expressing FcεRI and IgE were significantly increased compared to HC. Ex vivo, 1,25(OH)₂D₃ significantly decreased FcεRI expression on mDCs and surface‐bound IgE on mDCs and pDCs. Oral VD supplementation reduced expression of surface‐bound IgE on pDCs in children with AD. In summary, VD decreases the allergic phenotype of circulating DCs in children with AD, a potential mechanism for how VD supplementation may improve AD severity. Future studies are needed to further assess the role of VD supplementation as an immunomodulatory therapy for AD.     

Lipid Abnormalities in Persons Living With HIV Infection

Lipid abnormalities are prevalent among persons living with HIV infection and contribute to increasing the risk of cardiovascular events. Antiretroviral therapy (ART) is associated with lipid abnormalities, most commonly hypertriglyceridemia, but also increases in low-density lipoprotein cholesterol and total cholesterol. Different classes of ART, and different drugs within classes, have differing effects on lipid levels, but in general newer drugs have more favourable effects compared with older ones. Low-level inflammation and chronic immune activation act on lipids through a variety of mechanisms to make them more atherogenic. As a consequence, risk is higher than would be expected for any given cholesterol level. Clinical outcome trials of cholesterol-lowering therapies have not yet been completed in people living with HIV, so that treatment decisions depend on extrapolation from studies in uninfected populations. Traditional risk assessment tools underestimate cardiovascular risk in individuals with HIV. Statins are the mainstay of lipid-lowering drug treatment; however, drug–drug interactions with ART must be considered. Simvastatin and lovastatin are contraindicated in patients taking protease inhibitors, and the dose of atorvastatin and rosuvastatin should be limited to 40 mg and 10 mg/d with some ART combinations. Switching from older forms of ART to lipid-friendly newer ones is a useful strategy as long as virologic suppression is maintained, but adding a statin lowers low-density lipoprotein cholesterol more effectively. Studies indicate that lipid abnormalities are not treated as aggressively in individuals living with HIV as they are in uninfected people, making this an opportunity to improve care.     

Rates of reoperation and nonoperative intervention within 30 days of bariatric surgery

BackgroundComplications arising from laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic sleeve gastrectomy (LSG) are not insignificant and can necessitate additional invasive interventions or reoperations.ObjectivesIn this study, we identify early complications that result in nonoperative and operative interventions after LSG and LRYGB, the timeframe within which to expect them, and factors that influence the likelihood of their occurrence.SettingMulti-institutional database from across North America.MethodsData for this study were obtained from Metabolic and Bariatric Accreditation and Quality Improvement Program participant use files for 2015 and 2016. Statistical analysis was performed using STATA 15. Univariate analysis using Χ² for categoric data and independent t test for continuous data was performed to determine between group differences. Multivariable logistic regression analysis was used to identify predictors of operative and nonoperative reinterventions.ResultsIn 2015 and 2016, 243,747 underwent LRYGB or LSG, of which 3013 (1.24%) required a second operative procedure and 1536 (0.63%) required an invasive but nonoperative intervention. Complications occurred in 5.48% of LRYGB patients and 2.28% of LSG patients, the most common of which was bleeding. LSG was associated with far fewer nonoperative and operative interventions (.85% versus 2.2%, respectively) than LRYGB (.67% versus 2.5%). Renal insufficiency, including dialysis dependency, was an important predictor of reoperations among bariatric surgery patients. This was also true of nonoperative interventions; however, history of pulmonary embolism, and use of therapeutic anticoagulation were marginally stronger predictors.ConclusionsIn a representative, multinational sample, operative and nonoperative interventions were half as likely among LSG patients compared with LRYGB; however, overall rates still remained low. These findings, in conjunction with new efficacy data demonstrating comparable long-term weight loss between LRYGB and LSG, provide further support for the safety, effectiveness, and cost efficiency of LSG.     

Association between serum 25-hydroxyvitamin D concentration and severity of first-diagnosed bullous pemphigoid in older adults

BackgroundHigher vitamin D status has been associated with symptom improvement and decreased risk of various autoimmune disorders. Our objective was to determine whether higher serum 25-hydroxyvitamin D (25OHD) concentration correlated with less severe first-diagnosed bullous pemphigoid (BP) in older inpatients.MethodsThis cross-sectional study was performed from November 2012 to February 2014 among 30 consecutive older inpatients (21 women; mean ± SD, 83 ± 7 years; all Caucasian) with a de novo diagnosis of active BP recruited in the Department of Dermatology of Angers University Hospital, France. The severity of BP was graded clinically on the basis of i) the number of bullae during the first three days of hospitalization (grade 0–4, worse), and ii) the extent of the lesions (grade 0–5, worse).ResultsSixteen participants had ≤ 5 bullae at the time of diagnosis, 8 had 6–20 bullae, 3 had 20–50 bullae, and 3 had >50 bullae. The lesions were spread over 5 cutaneous areas in 5 participants (17%). The median 25OHD concentration was 23 [IQR, 16–42] nmol/L. Serum 25OHD concentration was inversely correlated with the bullae grade (ρ = − 0.38, p = 0.04) and the lesion extension grade (ρ = − 0.50, p = 0.005).ConclusionsHigher serum 25OHD concentration correlated with less severe BP prior to initiation of treatment among our sample of older inpatients. This result suggests that vitamin D may be involved in the pathophysiology of BP and could serve as prognostic biomarker of BP.