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.     

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Clinical and microbiological profile of adult inpatients with community acquired pneumonia in Ilorin,North Central,Nigeria

BackgroundThe optimal management of community acquired pneumonia (CAP) depends on the clinical and microbiological profile in the locality.ObjectivesTo determine the clinical and microbiological profile of patients admitted with CAP in Ilorin, Nigeria.MethodsOne hundred and two consenting consecutively selected patients with clinical and radiologic confirmation of CAP were recruited in 12 months. The socio-demographic, physical examination and laboratory/radiologic parameters were documented in a questionnaire. Microbiological evaluation of their sputum was done and blood samples were taken for complete blood count, culture, serum urea and serological evaluation for atypical bacteria and some viral pathogens.ResultsCAP constituted 5.9% of the total medical admissions during the one-year study period. The mean age of the patients was 49 ± 22 years with the largest frequency in those aged 65 years and above. The commonest symptoms were shortness of breath (96.1%) and cough (94.1%), with a median duration of 3 days from symptom onset to admission. Systemic hypertension was the commonest comorbid illness (25/102; 24.5%). Klebsiella pneumoniae was the predominant pathogen isolated (20/102; 28.1%). The susceptible antibiotics were Imipenem, Ceftazidime and Ceftriaxone. Intra-hospital mortality was 17.6%. CURB – 65 score of ≥ 2 and the presence of complications of CAP were the independent predictors of mortality.ConclusionCAP constitutes a significant disease burden in Ilorin, Nigeria. Typical bacteria accounted for over half of the pathogens isolated from the patients with gram negative agents predominating. This highlights a possible shift in the microbiological profile which could guide empirical treatment.     

Left Ventricular Systolic Dysfunction and Cardiovascular Outcomes in Tetralogy of Fallot: Systematic Review and Meta-analysis

BackgroundAlthough there are robust data about the pathophysiology and prognostic implications of left ventricular (LV) systolic dysfunction in patients with acquired heart disease, similar prognostic data about LV systolic dysfunction are sparse in the tetralogy of Fallot (TOF) population. The purpose of this study was to perform a meta-analysis of all studies that assessed the relationship between LV ejection fraction (LVEF) and cardiovascular adverse events (CAEs) defined as death, aborted sudden death, or sustained ventricular tachycardia.MethodsWe used random-effects models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsOf the 1,809 citations, 7 studies with 2,854 patients (age 28 ± 4 years) were included. During 5.6 ± 3.4 years' follow-up, there were 82 deaths, 17 aborted sudden cardiac deaths, and 56 sustained ventricular tachycardia events. Overall, CAEs occurred in 5.1% (144 patients). As a continuous variable, LVEF was a predictor of CAE (HR 1.29, 95% CI, 1.09-1.53, P = 0.001) per 5% decrease in LVEF. Similarly, LVEF < 40% was also a predictor of CAE (HR 3.22, 95% CI, 2.16-4.80, P < 0.001).ConclusionsLV systolic dysfunction was an independent predictor of CAE, and we observed a 30% increase in the risk of CAE for every 5% decrease in LVEF, and a 3-fold increase in the risk of CAE in patients with LVEF <40% compared with other patients. These findings underscore the importance of incorporating LV systolic function in clinical risk stratification of patients with TOF and the need to explore new treatment options to address this problem.     

Prenatal Substance Use and Perceptions of Parent and Partner Use Using the 4P’s Plus Screener

Maternal and Child Health Journal - Background Prenatal substance use screening is recommended. The 4 P’s Plus screener includes questions on perceived problematic substance use in parents...     

Attending Physicians' Perspectives of Resident Academic Half Day

Phenomenon: Academic health centers face significant challenges trying to improve medical education while meeting patient care needs. In response to problems with traditional forms of didactic education, many residency programs have transitioned to Academic Half Day (AHD), a curricular model in which learning is condensed into half-day blocks. In this model, trainees have protected educational time free from clinical responsibilities. However, an understanding of the impact on attending physicians and patient care when residents depart clinical sites for learning activities has not been well described. We sought to explore attending physicians’ perspectives when residents depart clinical sites to attend AHD. Approach: We performed a qualitative study with a grounded theory approach using individual semistructured interviews (December 2016–April 2017) of attending physicians who worked at inpatient and emergency department clinical sites from which residents departed to attend AHD. We used the constant comparative method, generating codes using an iterative approach and continuing sampling until saturation was reached. Major themes were identified and disagreements were resolved by consensus. Findings: Fifteen attending physicians from 6 clinical services were interviewed. Data analysis yielded 5 themes: emotional strain of workload, technology and systems challenges, patient safety and care concerns, disrupted resident learning, and the challenge to optimize resident education. Attending physicians, already working on busy services, felt frustrated and perceived having an increased workload when residents departed for AHD. They were concerned about safely entering orders in the electronic health record, impeded patient workflow, and further disruption of resident schedules already disrupted by duty hour restrictions and continuity clinic. Attending physicians described the importance of experiential learning from caring for patients and from structured didactic learning; however, the optimal balance was uncertain. Insights: We found that attending physicians experienced significant emotional strain, faced technological challenges, and were concerned about impeded workflow and patient safety when residents departed clinical sites for AHD. This is likely to be true whenever residents are pulled out of the clinical setting for any reason. Educators need to partner with hospital administrators to provide appropriate support for attending physicians when residents leave clinical sites, evaluate the effectiveness of different educational models, and determine how structured learning activities fit into the overall curriculum.     

Priming sentence comprehension in aphasia: effects of lexically independent and specific structural priming

Background & Aims: Impaired message-structure mapping results in deficits in both sentence production and comprehension in aphasia. Structural priming has been shown to facilitate syntactic production for persons with aphasia (PWA). However, it remains unknown if structural priming is also effective in sentence comprehension. We examined if PWA show preserved and lasting structural priming effects during interpretation of syntactically ambiguous sentences and if the priming effects occur independently of or in conjunction with lexical (verb) information.

Methods & Procedures: Eighteen PWA and 20 healthy older adults (HOA) completed a written sentence-picture matching task involving the interpretation of prepositional phrases (PP; the chef is poking the solider with an umbrella) that were ambiguous between high (verb modifier) and low attachment (object noun modifier). Only one interpretation was possible for prime sentences, while both interpretations were possible for target sentences. In Experiment 1, the target was presented immediately after the prime (0-lag). In Experiment 2, two filler items intervened between the prime and the target (2-lag). Within each experiment, the verb was repeated for half of the prime-target pairs, while different verbs were used for the other half. Participants’ off-line picture matching choices and response times were measured.

Results: After reading a prime sentence with a particular interpretation, HOA and PWA tended to interpret an ambiguous PP in a target sentence in the same way and with faster response times. Importantly, both groups continued to show this priming effect over a lag (Experiment 2), although the effect was not as reliable in response times. However, neither group showed lexical (verb-specific) boost on priming, deviating from robust lexical boost seen in the young adults of prior studies.

Conclusions: PWA demonstrate abstract (lexically-independent) structural priming in the absence of a lexically-specific boost. Abstract priming is preserved in aphasia, effectively facilitating not only immediate but also longer-lasting structure-message mapping during sentence comprehension.