Project description:The idea of "date" and "party" hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here, we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression; we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. However, we find significant correlations between interaction centrality and the functional similarity of the interacting proteins. We suggest that thinking in terms of a date/party dichotomy for hubs in protein interaction networks is not meaningful, and it might be more useful to conceive of roles for protein-protein interactions rather than for individual proteins.
Project description:The protein-protein interaction (PPI) networks are dynamically organized as modules, and are typically described by hub dichotomy: 'party' hubs act as intramodule hubs and are coexpressed with their partners, yet 'date' hubs act as coordinators among modules and are incoherently expressed with their partners. However, there remains skepticism about the existence of hub dichotomy. Since different algorithms and data sets were used in previous studies to test the model of hub classification, the conclusions may be largely influenced by the potential inherent biases. In this study, we evaluated two data sets of yeast interactome, and systematically investigated the behavior of hubs from multiple perspectives including co-expression patterns, topological roles and functional classifications. Our results revealed consistency between the two data sets, confirming the presence of hub dichotomy. Furthermore, we analyzed a human interactome data set, and demonstrated that the modular architecture of the PPI networks was more complicated than hub dichotomy.
Project description:The emergence of targeted therapy for patients with hematological diseases has permanently altered the therapeutic landscape. Immunochemotherapy regimes are now more and more being replaced by targeted therapies due to superior efficacy and better safety profiles. However, evolution and selection of subclones with continuous treatment leads to disease relapse and resistance toward these novel drugs. Venetoclax, the highly selective BCL-2 inhibitor (ABT-199), has an acceptable safety profile. To date, it has been approved for the treatment of first-line and relapsed/refractory chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, extension of indications can be expected in monotherapy and in combination regimens with promising outcomes in other hematological diseases. In this article, we describe the mechanism of action that stands behind the efficacy of venetoclax and provide a summary of available results from clinical trials.
Project description:Dobrava virus (DOBV) and Saaremaa virus (SAAV) are two closely related hantaviruses carried by different rodent species. The distinction of these two viruses has been a matter of debate. While the phylogenies based on the viral M segment sequences were repeatedly showing monophyly of SAAV strains, some trees based on the S segment sequences were not, thus causing questions on the demarcation between these two viruses. In order to clarify this issue, the current collection of the virus S segment sequences was subjected to extensive phylogenetic analysis using maximum likelihood, maximum parsimony and distant matrix methods. In all inferred phylogenies, the SAAV sequences were monophyletic and separated from DOBV sequences, thus supporting the view that SAAV and DOBV are distinct hantavirus species. Since collection of the S segment sequences used in this study "obeyed" the molecular clock, calculations of the split of DOBV and SAAV were now repeated resulting in an estimation of 3.0-3.7 MYA that is very close to the values obtained earlier.
Project description:The prevalence of type 2 diabetes (T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms, with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.
Project description:Plexiform leiomyomata are a histologically defined subgroup of benign uterine smooth muscle tumors based on their epitheliod cytology and abundant extracellular matrix. We used microarrays to compare plexiform leiomyomata to normal myometrium (smooth muscle of the uterine wall), typical leiomyomata, cellular or atypical leiomyomata and malignant leiomyosarcoma of the uterus. Keywords: tumor analysis
Project description:Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and treatment of COVID-19. This proposal is supported by the observation that (i) macrophages and T cells (including NK cells, cytotoxic killer cells and other immunocytes) release AA and other BALs especially in the lungs to inactivate various microbes; (ii) pro-inflammatory metabolites prostaglandin E2 (PGE2) and leukotrienes (LTs) and anti-inflammatory lipoxin A4 (LXA4) derived from AA (similarly, resolvins, protectins and maresins derived from eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) facilitate the generation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages respectively; (iii) AA, PGE2, LXA4 and other BALs inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) synthesis; (iv) mesenchymal stem cells (MSCs) that are of benefit in COVID-19 elaborate LXA4 to bring about their beneficial actions and (v) subjects with insulin resistance, obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and the elderly have significantly low plasma concentrations of AA and LXA4 that may render them more susceptible to SARS-CoV-2 infection and cytokine storm that is associated with increased mortality seen in COVID-19. Statins, colchicine, and corticosteroids that appear to be of benefit in COVID-19 can influence BALs metabolism. AA, and other BALs influence cell membrane fluidity and thus, regulate ACE-2 (angiotensin converting enzyme-2) receptors (the ligand through which SARS-CoV2 enters the cell) receptors. These observations lend support to the contention that administration of BALs especially, AA could be of significant benefit in prevention and management of COVI-19 and other enveloped viruses.
Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) are a unique class of antineoplastic agents that function by inducing synthetic lethality. Synthetic lethality occurs when PARPi and either another agent or an underlying genetic alteration together lead to overwhelming DNA damage and ultimately cell death. PARPi first showed promise as a cancer therapy in patients with BRCA1/2 mutations and have become part of standard treatment for breast and ovarian cancer. In prostate cancer, two PARPi, rucaparib and olaparib, have been FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). While both agents are approved for tumors with BRCA1/2 alterations, for olaparib the indication is also expanded to patients with 12 other homologous recombination deficiency (HRD) gene alterations including ATM and PALB2. PARPi differ in their pharmacokinetics and pharmacodynamics, and additional studies are being conducted with niraparib, veliparib, and talazoparib in prostate cancer. While PARPi are fairly well tolerated, common toxicities include hematologic (anemia/thrombocytopenia) and gastrointestinal effects (nausea/vomiting). Ongoing studies are being conducted combining PARPi with other agents in patients with and without HRD alterations. Early data are promising for the combination of PARPi with second-generation antiandrogens and with immunotherapy. As additional trials are developed and reported, the hope is that the patient population who may benefit from PARPi will continue to expand.
Project description:Psoriasis is a chronic, immune-mediated, inflammatory, and debilitating skin disease with significant impact on patients' quality of life. Its pathogenesis is complex and not yet fully understood. However, the IL-23/IL-17 axis is currently considered the main pathogenic pathway in psoriasis. Guselkumab is a fully human immunoglobulin G1 λ (IgG1λ) monoclonal antibody (mAb) that binds to the p19 subunit of IL-23. It is the first of its class, already approved by the US Food and Drug Administration (FDA), as well as the European Medicines Agency (EMA) for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for either systemic therapy or phototherapy. Several clinical trials have demonstrated potential benefits of guselkumab over other already approved immunomodulators in terms of safety and efficacy. The results of the head-to-head trial ECLIPSE were recently released and are addressed in this review. They contribute to the increasing confidence in guselkumab, demonstrating great potential for long-term treatment of psoriasis. However, further long-term data and additional comparative studies will be essential for positioning guselkumab in the therapeutic armamentarium for psoriasis.
Project description:Atopic dermatitis is a prevalent, inflammatory skin disease that presents with an eczematous, itchy rash. As of late, there have been many emerging monoclonal antibody inhibitor and small molecule therapies that have changed the course of eczema treatment. One of the treatments in the pipeline for atopic dermatitis is interleukin 13 monoclonal antibody inhibitor, lebrikizumab. As interleukin 13 has been identified as a pro-inflammatory cytokine in the immunological cascade of eczema, it is thought that lebrikizumab can be a great treatment choice for patients with atopic dermatitis. Lebrikizumab is currently being investigated in several studies. Thus far, lebrikizumab for the treatment of eczema has been found to be efficacious; in particular, a rapid response of pruritus improvement has been demonstrated in as early as 2 days. Additionally, it is well tolerated and has an acceptable safety profile, with reports suggesting that are decreased risks of infection when compared to dupilumab. In this review, we aim to summarize the current understanding of lebrikizumab in terms of the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, efficacy and safety, and drug indications.