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.     

Isolated Anisocoria as a Presenting Stroke Code Symptom is Unlikely to Result in Alteplase Administration

Background

Acute stroke codes may be activated for anisocoria, but how often these codes lead to a final stroke diagnosis or alteplase treatment is unknown. The purpose of this study was to assess the frequency of anisocoria in stroke codes that ultimately resulted in alteplase administration.

Classification and cyclic fatigue evaluation of new kinematics for endodontic instruments

This study evaluated the effect of new motions of the motor TriAuto ZX2 on the cyclic fatigue of endodontic instruments. Vortex Blue 35.06 instruments were divided into four groups (n = 10) and tested for fatigue in a curved artificial canal (90° and 2 mm radius) using the following motions: continuous rotation (CR), Optimum Torque Reverse (OTR) set at 180° and the Optimum Glide Path (OGP), which was tested at 90° and 240°. The time to fracture (TTF) and the lengths of the fractured fragments were recorded. The mean TTF was significantly different among the groups (anova , P < 0.05): OGP 90° (213.39 ± 27.45), OTR 180° (121.24 ± 17.03), OGP 240° (45.24 ± 5.61) and CR (8.43 ± 1.27). Weibull analysis confirmed the shortest life expectancy for CR and the longest survival for OGP at 90°. The resistance to fatigue was affected by motions and pre‐set angles. The proprietary movements that are currently available for endodontic instruments were classified according to their kinematics.     

Tauchunfälle

Notfall + Rettungsmedizin - Tauchunfälle sind vergleichsweise selten und stellen (Erst‑)Helfer vor besondere Herausforderungen. Sie müssen schnell und kompetent behandelt werden, da...     

Operative Behandlung von Rektumkarzinomen im Vergleich

BACKGROUND: The laparoscopic resection of rectal cancer shows morbidity and oncological safety comparable to the open approach, but morbidity increases after conversion to open resection. No oncological long-term results are available for the latter patients. METHODS: From 01/01/2000-31/12/2002, patients with curatively resected rectal cancer enrolled in a observational study were evaluated for morbidity, mortality, tumor- and local recurrence rate, paying attention to patients with conversion from laparoscopic to open resection. RESULTS: 237 (3.3%) of 7,189 patients underwent laparoscopic resection (ITT). These patients showed significantly more T1/2 tumors (P<0.001) in earlier UICC stages (P<0.001) than open resected patients. 35 (14.8%) of 237 laparoscopic procedures were converted. Compared with patients receiving complete laparoscopic or open resection, these patients showed significantly higher frequencies of intraoperative (P<0.001) and general postoperative complications (P=0.003) as well as the highest overall morbidity (P=0.031). After a median follow-up of 30.1 months, the highest 5-year local recurrence rate was found in the converted group (16.0%). The laparoscopically resected patients showed a local recurrence rate of 3.3%, patients with open resection of 12.4% (P=0.082). The disease-free survival rate did not differ between the groups (P=0.585). CONCLUSION: Laparoscopic resection of rectal cancer provides oncological results similar to open resection. After conversion, the short and oncological long-term outcomes were worse. Considering a conversion rate of 15%, only a strict indication for the laparoscopic approach can be allowed, and laparoscopic resection should be performed at centers.     

Experimental evaluation of three osteosynthesis devices used for stabilizing condylar fractures of the mandible.

INTRODUCTION: The purpose of the study is to evaluate experimentally the quality of the primary stability achieved in treating low subcondylar fractures by means of three different osteosynthesis devices. MATERIAL AND METHODS: The devices, a standard four-hole plate, an axial lag screw and a three-dimensional rectangular plate were tested on fresh isolated human mandibles. Testing was done on a test bench by reproducing static biting exercises between the first molars on the side of the fracture. The quality of the osteosynthesis was assessed by measuring the macroscopic amount of fragment displacement and on the device's ability to diffuse the mechanical strain within the fractured area by photoelastic stress analysis. RESULTS: The straight plates provided the worst restoration. This was explained by the unfavourable position of the plate along compression lines. The axial lag screws allowed average stability. This was due to the difficulty of intra-medullary positioning of the screw, and by the compression of the fracture line. Rectangular plates allowed good stability associated with rather good restitution of the strains. These good results were assigned to the shape of the plate, one of its arms approximating the tensile strain lines. CONCLUSION: Positioning and shape of the osteosynthesis device are of prime importance for condylar fracture stabilization. None of the three tested devices was optimal but the three-dimensional plate was the best. There is a need to develop the geometry of new plates.     

Increased Levels of Soluble Tumour Necrosis Factor Receptor-I (P55) and Decreased IgG1 Reactivities in HIV-1 Patients with Cytomegalovirus Disease

The purpose of the study was to investigate potential associations between tumour necrosis factor (TNF), soluble TNF receptors (sTNF-Rs), immunoglobulin (Ig)G subclasses and development of cytomegalovirus (CMV) disease amongst human immunodeficiency virus (HIV)-1 patients. We enrolled HIV-1 patients with CD4 counts less than 100/μl in a prospective study and followed them over 1 year for development of CMV disease. Concentrations of TNF, sTNF-RI, sTNF-RII and IgG subclass reactivities were measured by ELISA; levels of CMV pp65 antigenaemia were determined as numbers of pp65 expressing cells/100 000 cells and were measured by staining of leucocytes; and HIV-1 RNA loads were measured by polymerase chain reaction (PCR). Eighteen patients studied with CMV disease had higher levels of sTNF-RI than 18 similar patients without CMV disease. Concentrations of sTNF-RI correlated with levels of CMV antigenaemia in blood samples collected before the development of CMV disease. Patients with CMV disease had lower levels of IgG₁ reactivities to CMV than patients without CMV disease. We conclude that increased levels of sTNF-RI and decreased IgG₁ reactivities are associated with an increased risk of development of CMV disease among HIV-1 patients.