Synthetic, enzyme kinetic, and protein crystallographic studies of C-[béta]-D-glucopyranosyl pyrroles and imidazoles reveal and explain low nanomolar inhibition of human liver glycogen phosphorylase

LBK

[Role of loco-regional treatments for patients with breast cancer liver metastases].

Breast cancer liver metastases (BCLM) are not uncommon (about 18\% of cases): although some patients have been reported as still living after 25 months, median survival after hormonal- or chemotherapy is 6-14 months. In recent years, new chemotherapy regimens and molecular targeted therapies have given medical oncologists reason to believe that metastatic disease can be eradicated, or at least controlled for prolonged periods. In an attempt to improve survival, consideration has also been given to loco-regional treatments such as hepatic resection and radio-frequency ablation, which have been associated with better outcomes in selected patients. This review considers the role of two loco-regional approaches in a multidisciplinary perspective in the treatment of single or multiple breast cancer metastases limited to the liver. An expanded role for hepatic resection and ablation is being investigated. We assessed available data in the literature to determine their role on survival outcomes. They suggest that loco-regional treatments might be of significant benefit in a selected group of women with BCLM, but the role of these local treatments in multimodality treatment of liver metastases remains controversial. It can generally be said that loco-regional treatments can improve overall survival, with no mortality and less than 20\% morbidity in patients at low surgical risk; however, they should only be considered cytoreductive treatments and, as such, always need to be integrated with systemic therapy

“Role of loco-regional treatments for patients with breast cancer liver metastases”

Breast cancer liver metastases (BCLM) are not uncommon (about 18\% of cases): although some patients have been reported as still living after 25 months, median survival after hormonal- or chemotherapy is 6-14 months. In recent years, new chemotherapy regimens and molecular targeted therapies have given medical oncologists reason to believe that metastatic disease can be eradicated, or at least controlled for prolonged periods. In an attempt to improve survival, consideration has also been given to loco-regional treatments such as hepatic resection and radio-frequency ablation, which have been associated with better outcomes in selected patients. This review considers the role of two loco-regional approaches in a multidisciplinary perspective in the treatment of single or multiple breast cancer metastases limited to the liver. An expanded role for hepatic resection and ablation is being investigated. We assessed available data in the literature to determine their role on survival outcomes. They suggest that loco-regional treatments might be of significant benefit in a selected group of women with BCLM, but the role of these local treatments in multimodality treatment of liver metastases remains controversial. It can generally be said that loco-regional treatments can improve overall survival, with no mortality and less than 20\% morbidity in patients at low surgical risk; however, they should only be considered cytoreductive treatments and, as such, always need to be integrated with systemic therapy

The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics

As a major arm of the cellular immune response, CD4+ T cells are important in the control and clearance of infections. Primarily described as helpers, CD4+ T cells play an integral role in the development and activation of B cells and CD8+ T cells. CD4+ T cells are incredibly heterogeneous, and can be divided into six main lineages based on distinct profiles, namely T helper 1, 2, 17 and 22 (Th1, Th2, Th17, Th22), regulatory T cells (Treg) and T follicular helper cells (Tfh). Recent advances in structural biology have allowed for a detailed characterisation of the molecular mechanisms that drive CD4+ T cell recognition. In this review, we discuss the defining features of the main human CD4+ T cell lineages and their role in immunity, as well as their structural characteristics underlying their detection of pathogens

Non-contact Current Transfer Induces the Formation and Improves the X-ray Diffraction Quality of Protein Crystals

The effect of non-contact current transfer on the crystallization of three model proteins (hen egg white lysozyme, bovine pancreatic ribonuclease A, and human recombinant insulin) was investigated using a prototype ion-generator device. The device can produce an equivalent of microcurrent that can be transmitted in a contactless manner by spraying negatively charged ions and using available air gases (O-2) as a transfer medium. From a crystallographic perspective, non-contact current transfer technology clearly enhanced the crystal formation process of these three proteins, as evidenced by the high crystallization speed and crystal quality. The quality and X-ray diffraction patterns of lysozyme crystals grown in the presence and absence of the device's microcurrent were analyzed. Our results indicate a significant positive effect on the quality of the X-ray diffraction pattern after non-contact current transfer, highlighting the value of this technique in protein crystallization

van der Waals interactions govern C-β-D-glucopyranosyl triazoles’ nM inhibitory potency in human liver glycogen phosphorylase

3-(C-Glucopyranosyl)-5aryl-1,2,4-triazoles with an aryl moiety larger than phenyl have been shown to have strong inhibitory potency (Ki values in the range of upper nM) for human liver glycogen phosphorylase (hlGP), a pharmacologically relevant target for diabetes type 2. In this study we investigate in a comparative manner the inhibitory effect of the above triazoles and their respective imidazoles on hlGPa. Kinetic studies show that the imidazole derivatives are 6–8 times more potent than their corresponding triazoles. We also seek to answer how the type of the aryl moiety affects the potency in hlGPa, and by determination of the crystal structure of rmGPb in complex with the triazole derivatives the structural basis of their inhibitory efficacy is also elucidated. Our studies revealed that the van der Waals interactions between the aryl moiety and residues in a hydrophobic pocket within the active site are mainly responsible for the variations in the potency of these inhibitors. © 2017 Elsevier Inc