Adherence to adjuvant hormonal therapy in localised breast cancer.

BACKGROUND: Hormonal therapies are the cornerstone of systemic adjuvant treatment of oestrogen receptor (ER) positive breast cancer. The full benefit of this treatment is obtained with long-term adherence. However, discontinuation of hormonal therapy is common. Factors associated with non-compliance to therapy are complex and worth of detailed evaluation. PATIENTS AND METHODS: A retrospective analysis of medical records of 284 early ER-positive breast cancer patients prescribed adjuvant hormonal therapy during a 5-year period in a single centre was undertaken. Characteristics of the patients and their disease as well as adherence to therapy and continuation at 1 and 3 years were recorded. The group of patients that were on treatment at 3 years and the group that had discontinued therapy before 3 years were compared to identify differences predicting lack of adherence. RESULTS: The discontinuation rate of hormonal therapy at 1 year was 13%, and the discontinuation rate at 3 years was 21.2%. Patient age and menopause status were not associated with hormone therapy adherence at 3 years. The type of hormonal therapy (aromatase inhibitor or tamoxifen) was also not associated with adherence. In contrast, patients that received adjuvant chemotherapy before starting hormonal therapy had a higher adherence to hormonal therapy (86.9% at 3 years vs. 75.7% in patients that had not received adjuvant chemotherapy, χ2 p = 0.04). Among co-morbidities, patients with a concomitant diagnosis of psychiatric disease at the time of breast cancer diagnosis were at increased risk of hormone therapy non-adherence. Progression-free survival and overall survival were inferior in the non-adherent group compared with the patients who continued their hormonal therapy at 3 years. CONCLUSION: Adjuvant chemotherapy is associated with better subsequent adherence to hormonal therapy in early breast cancer patients. On the other hand, psychiatric co-morbidities are associated with worse adherence. De-escalation of adjuvant therapy guided by genomic tests leads to a significant percentage of early ER-positive breast cancer patients not receiving chemotherapy. Non-adherence to hormonal therapy would leave a subset of these patients with no adjuvant systemic therapy. The current results will guide efforts to increase compliance to hormonal therapies in specific groups of patients.

Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration.

Aggregates or oligomeric forms of many intrinsically disordered proteins (IDPs), including α-synuclein, are hallmarks of neurodegenerative diseases, like Parkinson's and Alzheimer's disease, and key contributors to their pathogenesis. Due to their disordered nature and therefore lack of defined drug-binding pockets, IDPs are difficult targets for traditional small molecule drug design and are often referred to as "undruggable". The 20S proteasome is the main protease that targets IDPs for degradation and therefore small molecule 20S proteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified thus far. Herein, we synthesized and evaluated a library of dihydroquinazoline analogues and discovered several promising new 20S proteasome activators. Further testing of top hits revealed that they can enhance 20S mediated degradation of α-synuclein, the IDP associated with Parkinson's disease.

Triflic anhydride mediated synthesis of 3,4-dihydroquinazolines: a three-component one-pot tandem procedure.

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.

Evaluation of PCR-based preimplantation genetic diagnosis applied to monogenic diseases: a collaborative ESHRE PGD consortium study.

Preimplantation genetic diagnosis (PGD) for monogenic disorders currently involves polymerase chain reaction (PCR)-based methods, which must be robust, sensitive and highly accurate, precluding misdiagnosis. Twelve adverse misdiagnoses reported to the ESHRE PGD-Consortium are likely an underestimate. This retrospective study, involving six PGD centres, assessed the validity of PCR-based PGD through reanalysis of untransferred embryos from monogenic-PGD cycles. Data were collected on the genotype concordance at PGD and follow-up from 940 untransferred embryos, including details on the parameters of PGD cycles: category of monogenic disease, embryo morphology, embryo biopsy and genotype assay strategy. To determine the validity of PCR-based PGD, the sensitivity (Se), specificity (Sp) and diagnostic accuracy were calculated. Stratified analyses were also conducted to assess the influence of the parameters above on the validity of PCR-based PGD. The analysis of overall data showed that 93.7% of embryos had been correctly classified at the time of PGD, with Se of 99.2% and Sp of 80.9%. The stratified analyses found that diagnostic accuracy is statistically significantly higher when PGD is performed on two cells versus one cell (P=0.001). Se was significantly higher when multiplex protocols versus singleplex protocols were applied (P=0.005), as well as for PGD applied on cells from good compared with poor morphology embryos (P=0.032). Morphology, however, did not affect diagnostic accuracy. Multiplex PCR-based methods on one cell, are as robust as those on two cells regarding false negative rate, which is the most important criteria for clinical PGD applications. Overall, this study demonstrates the validity, robustness and high diagnostic value of PCR-based PGD.

A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurones.

BACKGROUND: Whole cell patch clamp recording and intracellular Ca2+ imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red Sea soft corals. The aim of the project was to identify compounds that would alter the excitability of DRG neurones. RESULTS: Crude extracts of Sarcophyton glaucum and Lobophyton crassum attenuated spike frequency adaptation causing DRG neurones to switch from firing single action potentials to multiple firing. The increase in excitability was associated with enhanced KCl-evoked Ca2+ influx. The mechanism of action of the natural products in the samples from the soft corals involved inhibition of voltage-activated K+ currents. An active component of the crude marine samples was identified as 3-carboxy-1-methyl pyridinium (trigonelline). Application of synthetic 3-carboxy-1-methyl pyridinium at high concentration (0.1 mM) also induced multiple firing and reduced voltage-activated K+ current. The changes in excitability of DRG neurones induced by 3-carboxy-1-methyl pyridinium suggest that this compound contributes to the bioactivity produced by the crude extracts from two soft corals. CONCLUSION: Sarcophyton glaucum and Lobophyton crassum contain natural products including 3-carboxy-1-methyl pyridinium that increase the excitability of DRG neurones. We speculate that in addition to developmental control and osmoregulation these compounds may contribute to chemical defenses.

Endovenous saphenous ablation corrects the hemodynamic abnormality in patients with CEAP clinical class 3-6 CVI due to superficial reflux.

This investigation was designed to determine whether minimally invasive radiofrequency or laser ablation of the saphenous vein corrects the hemodynamic impact and clinical symptoms of chronic venous insufficiency (CVI) in CEAP clinical class 3-6 patients with superficial venous reflux. Patients with CEAP clinical class 3-6 CVI were evaluated with duplex ultrasound and air plethysmography (APG) to determine anatomic and hemodynamic venous abnormalities. Patients with an abnormal (>2 mL/second) venous filling index (VFI) and superficial venous reflux were included in this study. Saphenous ablation was performed utilizing radiofrequency (RF) or endovenous laser treatment (EVLT). Patients were reexamined within 3 months of ablation with duplex to determine anatomic success of the procedure, and with repeat APG to determine the degree of hemodynamic improvement. Venous clinical severity scores (VCSS) were determined before and after saphenous ablation. Eighty-nine limbs in 80 patients were treated with radiofrequency ablation (RFA) (n = 58), or EVLT (n = 31). The average age of patients was 55 years and 66% were women. There were no significant differences in preoperative characteristics between the groups treated with RFA or EVLT. Postoperatively, 86% of limbs demonstrated near total closure of the saphenous vein to within 5 cm of the saphenofemoral junction. Eight percent remained open for 5-10 cm from the junction, and 6% demonstrated minimal or no saphenous ablation. The VFI improved significantly after ablation in both the RF and EVLT groups. Postablation, 78% of the 89 limbs were normal, with a VFI <2 mL/second, and 17% were moderately abnormal, between 2 and 4 mL/second. VCSS scores (11.5 +/-4.5 preablation) decreased significantly after ablation to 4.4 +/-2.3. Minimally invasive saphenous ablation, using either RFA or EVLT, corrects or significantly improved the hemodynamic abnormality and clinical symptoms associated with superficial venous reflux in more than 90% of cases. These techniques are useful for treatment of patients with more severe clinical classes of superficial CVI.