Overcoming phenotypic switching: targeting protein-protein interactions in cancer

Alternative protein-protein interactions (PPIs) arising from mutations or post-translational modifications (PTMs), termed phenotypic switching (PS), are critical for the transmission of alternative pathogenic signals and are particularly significant in cancer. In recent years, PPIs have emerged as promising targets for rational drug design, primarily because their high specificity facilitates targeting of disease-related signaling pathways. However, obstacles exist at the molecular level that arise from the properties of the interaction interfaces and the propensity of small molecule drugs to interact with more than one cleft surface. The difficulty in identifying small molecules that act as activators or inhibitors to counteract the biological effects of mutations raises issues that have not been encountered before. For example, small molecules can bind tightly but may not act as drugs or bind to multiple sites (interaction promiscuity). Another reason is the absence of significant clefts on protein surfaces; if a pocket is present, it may be too small, or its geometry may prevent binding. PS, which arises from oncogenic (alternative) signaling, causes drug resistance and forms the basis for the systemic robustness of tumors. In this review, the properties of PPI interfaces relevant to the design and development of targeting drugs are examined. In addition, the interactions between three tyrosine kinase inhibitors (TKIs) employed as drugs are discussed. Finally, potential novel targets of one of these drugs were identified in silico

Sequential treatment with teriparatide and strontium ranelate in a postmenopausal woman with atypical femoral fractures after long-term bisphosphonate administration

AbstrAct ObJEctIVE: Despite the existence of numerous case series, no evidenced-based medical management for atypical fractures associated with bisphosphonate (bP) treatment has been established. DEsIGN: We report the outcome of teriparatide (trP) administration followed by strontium ranelate (sr) in a woman with a complete and an incomplete contralateral atypical fracture of the femoral diaphysis (AFF) associated with bP treatment. the spontaneous complete AFF was managed with intramedullary nailing, discontinuation of bP and initiation trP. rEsULts: Eleven months later, she suffered a contralateral incomplete AFF. At the completion of the trP treatment, she had only slight discomfort in the femur with the incomplete AFF. bMD testing revealed increase of 7.61% at the lumbar spine (Ls) and 0.8% at the hip. Following trP, 1-year sr treatment resulted in further bMD increase of 9.2% at the Ls and 1.4% in the hip, while she does not report any pain. bone markers remain within the normal range. cONcLUsION: Our case indicates that sequential therapy with trP and sr in cases of AFF might be a rational treatment option. However, there is a need for additional information concerning the effect of trP and sr, given alone or sequentially, in these patients in order to incorporate these drugs into the management of AFF

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma

The authors acknowledge Mr Aivaras Cepelis for his contribution during the development of the manuscript. The authors thank Ms Pui Yee Lai (M.A.), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication.Peer reviewe

Characterization of patients in the International Severe Asthma Registry with high steroid exposure who did or did not initiate biologic therapy

Peer reviewedPostprin

Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe

Association between pre-biologic T2-biomaker combinations and response to biologics in patients with severe asthma

Funding This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global (OPCG) and AstraZeneca Ltd. No funding was received by the OPRI for its contribution. The International Severe Asthma Registry (ISAR) is operated by OPCG and co-funded by OPCG and AstraZenecaPeer reviewe

Pre-treatment and extraction techniques for recovery of added value compounds from wastes throughout the agri-food chain

The enormous quantity of food wastes discarded annually force to look for alternatives for this interesting feedstock. Thus, food bio-waste valorisation is one of the imperatives of the nowadays society. This review is the most comprehensive overview of currently existing technologies and processes in this field. It tackles classical and innovative physical, physico-chemical and chemical methods of food waste pre-treatment and extraction for recovery of added value compounds and detection by modern technologies and are an outcome of the COST Action EUBIS, TD1203 Food Waste Valorisation for Sustainable Chemicals, Materials and Fuels

Tolerance of Tall Fescue (<i>Festuca arundinacea</i> Schreb.) Growing in Extensive Green Roof Systems to Saline Water Irrigation with Varying Leaching Fractions

As urbanization intensifies environmental challenges in contemporary cities, widespread green roof installations emerge as a potential solution. This study explores irrigating tall fescue (Festuca arundinacea Schreb.) turfgrass with saline water in extensive green roof systems, aiming to conserve freshwater resources. The objectives include determining the period of saline water tolerance and identifying the leachate electrical conductivity threshold affecting tall fescue’s green coverage. This greenhouse study comprised 24 lysimeters equipped with extensive green roof layering. Treatments included three NaCl irrigation solutions with an electrical conductivity of 3 dS m−1, 6 dS m−1, and 9 dS m−1, while tap water served as the control. Additionally, irrigation treatments were applied at two different regimes, resulting in an average leaching fraction of 0.3 for the low irrigation regime and 0.5 for the high irrigation regime. Tall fescue’s tolerance to saline water was evaluated through the determination of green turf cover (GTC) as well as the clipping dry weight and the leachate electrical conductivity (ECL) draining from the lysimeters. It was found that tall fescue turfgrass growing in extensive green roof systems can tolerate irrigation with water of electrical conductivity up to 9 dS m−1 for extended periods, approximating three months, without GTC declining below 90%, provided that a minimum leaching of 30% is maintained. Furthermore, irrigating with water at 9 dS m−1 resulted in a 24.5% reduction in cumulative clipping dry weight over the four-month study period. The regression analysis between GTC and ECL highlighted a substantial decline in GTC when ECL surpassed the critical threshold of 12.5 dS m−1