Glucocorticoids promote breast cancer metastasis

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy(1-3). Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade(4), remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.Peer reviewe

PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer.

The protein tyrosine phosphatase SHP2 activates oncogenic pathways downstream of most receptor tyrosine kinases (RTK) and has been implicated in various cancer types, including the highly aggressive subtype of triple-negative breast cancer (TNBC). Although allosteric inhibitors of SHP2 have been developed and are currently being evaluated in clinical trials, neither the mechanisms of the resistance to these agents, nor the means to circumvent such resistance have been clearly defined. The PI3K signaling pathway is also hyperactivated in breast cancer and contributes to resistance to anticancer therapies. When PI3K is inhibited, resistance also develops for example via activation of RTKs. We therefore assessed the effect of targeting PI3K and SHP2 alone or in combination in preclinical models of metastatic TNBC. In addition to the beneficial inhibitory effects of SHP2 alone, dual PI3K/SHP2 treatment decreased primary tumor growth synergistically, blocked the formation of lung metastases, and increased survival in preclinical models. Mechanistically, transcriptome and phospho-proteome analyses revealed that resistance to SHP2 inhibition is mediated by PDGFRβ-evoked activation of PI3K signaling. Altogether, our data provide a rationale for co-targeting of SHP2 and PI3K in metastatic TNBC

Similarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS.

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection

High-Performance Computing for SKA Transient Search: Use of FPGA based Accelerators -- a brief review

This paper presents the High-Performance computing efforts with FPGA for the accelerated pulsar/transient search for the SKA. Case studies are presented from within SKA and pathfinder telescopes highlighting future opportunities. It reviews the scenario that has shifted from offline processing of the radio telescope data to digitizing several hundreds/thousands of antenna outputs over huge bandwidths, forming several 100s of beams, and processing the data in the SKA real-time pulsar search pipelines. A brief account of the different architectures of the accelerators, primarily the new generation Field Programmable Gate Array-based accelerators, showing their critical roles to achieve high-performance computing and in handling the enormous data volume problems of the SKA is presented here. It also presents the power-performance efficiency of this emerging technology and presents potential future scenarios.Comment: Accepted for JoAA, SKA Special issue on SKA (2022

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Noise Induced Hearing Loss with Tinnitus: Does TRT Help?

Introduction To determine if hearing augmentation and tinnitus retraining therapy (TRT) helps in cases of Tinnitus with Noise induced hearing loss (NIHL) and does degree of hearing loss, severity or duration of tinnitus affect recovery  Materials and Methods A prospective study was done on 100 patients of NIHL with tinnitus from Jan 14-Jul 15. Degree of hearing loss was assessed. Tinnitus severity was scored on Tinnitus handicap inventory (THI) scale as Slight, Mild, Moderate, severe or catastrophic and patients were subjected to TRT. Patients scored after 1 year of TRT. A relation between tinnitus severity, duration and degree of hearing loss on recovery from tinnitus was analysed. Result 62 of the 100 patients improved following TRT. Discussion In 100 patients THI scores improved from a mean of 63.12 (SD-21.12) to 38.16 (SD-18.21). Mean difference between pre and post-intervention THI scores was 24.96 (SD-17.97). Improvement was significant in severe or profound hearing loss (P<.001). Tinnitus severity was slight, mild, moderate, severe or catastrophic on THI. Following TRT, 82.35% with Catastrophic, 70.96% with severe, 52.63% with moderate, 20% with mild tinnitus improved. 1 patient with slight tinnitus did not improve. Based on duration of tinnitus three groups made; 0-6 months, 6-12 months and >12 months. All groups showed improvement. Reduction in Post-TRT THI was significant but did not show any difference among groups. Conclusion TRT helps in tinnitus with NIHL particularly if hearing loss is severe. Severe or catastrophic tinnitus patients experience greater improvement. Duration of tinnitus has no impact

Firms’ Obligation to Stakeholders: AI and IPR

The application of Artificial Intelligence (AI) systems is not going to go away; so, society needs to engage with the emerging technology. Moreover, the wide range of activities that could benefit from AI systems suggest that societal engagement between stakeholders, developers and government is a strong requirement for social trust so as not to undermine societal cohesion. Viewing the actions of AI systems through ethical lenses will help to resolve societal tensions and issues. However, this is not enough to relieve society’s concerns about AI systems; co-control of AI systems between developers and the government is one way to ease these concerns, which will raise the issue of Intellectual Property Rights (IPR) control. Governments must move from being promoters and guarantors of emerging technologies to balancing the societal needs of multi-stakeholders