• Pluripotent hematopoietic stem cells augment alpha-adrenergic receptor-mediated contraction of pulmonary artery and contribute to the pathogenesis of pulmonary hypertension

  Hashimoto, R; Lanier, GM; Dhagia, V; Joshi, SR; Jordan, Allan M; Waddell, Ian D; Tuder, R; Stenmark, KR; Wolin, MS; McMurtry, IF; et al. (2020)

  Pulmonary hypertension (PH) is a multicellular and progressive disease with a high mortality rate. Among many cell types, hematopoietic stem cells (HSCs) are incriminated in the pathogenesis of PH. However, our understanding of the mechanisms that increase HSCs in blood and lungs of hypertensive animals or patients and the role played by HSCs in the pathogenesis of PH remains elusive. Studies suggest that glycolysis is critical for the survival and growth of HSCs. In various cell types from hypertensive lungs of animals and patients, glycolysis and the glucose-6-phosphate dehydrogenase (G6PD) activity are increased. Herein, we demonstrated in mice that chronic hypoxia increased HSCs (CD34+, CD117+, CD133+, CD34+/CD117+, and CD34+/CD133+) in bone marrow and blood and around hypertensive pulmonary arteries in a time-dependent manner. Intriguingly, we found fewer CD133+ cells in the bone marrow of C57BL/6 mice compared with Sv129J mice, and C57BL mice developed less severe chronic hypoxia-elicited PH and heart failure than Sv129J mice. Similarly, the numbers of CD34+ and CD117+ cells in blood of patients with pulmonary arterial hypertension (PAH) were higher (>3-fold) compared with healthy individuals. By allogeneic bone marrow transplantation, we found that GFP+ bone marrow cells infiltrated the lungs and accumulated around the pulmonary arteries in lungs of hypoxic mice, and these cells contributed to increased α-adrenergic receptor-mediated contraction of the pulmonary artery cultured in hypoxia. Inhibition of G6PD activity with (3β,5α)-3,21-dihydroxypregnan-20-one, a novel and potent G6PD inhibitor, decreased HSCs in bone marrow, blood, and lungs of hypoxic mice and reduced α-agonist-induced contraction of the pulmonary artery and established hypoxia-induced PH. We did not observe CD133+ cells around the pulmonary arteries in the lungs of chronically hypoxic G6PD-deficient mice. Furthermore, knockdown of G6PD and inhibition of G6PD activity: 1) downregulated canonical and noncanonical Wnt and Fzd receptors genes; 2) upregulated Bmpr1a; 3) decreased Cxcl12, and 4) reduced HSC (CD117+ and CD133+) numbers. In all, our findings demonstrate unexpected function for bone marrow-derived HSCs in augmenting α-adrenergic receptor-mediated contraction of pulmonary arteries and remodeling of pulmonary arteries that contribute to increase pulmonary vascular resistance in PAH patients and hypoxic mice and suggest that G6PD, by regulating expression of genes in the WNT and BMPR signaling, contributed to increase and release of HSCs from the bone marrow in response to hypoxic stimuli.
• The Shb scaffold binds the Nck adaptor protein, p120 RasGAP and Chimaerins and thereby facilitates heterotypic cell segregation by the receptor EphB2

  Wagner, MJ; Hsiung, MS; Gish, GD; Bagshaw, RD; Doodnauth, SA; Soliman, MA; Jorgensen, Claus; Tucholska, M; Rottapel, R; Princess Margaret Cancer Centre, CanadaLunenfeld-Tanenbaum Research Institute, Canada (2020)

  Eph receptors are a family of receptor tyrosine kinases that control directional cell movement during various biological processes, including embryogenesis, neuronal pathfinding, and tumor formation. The biochemical pathways of Eph receptors are context-dependent in part because of the varied composition of a heterotypic, oligomeric, active Eph receptor complex. Downstream of the Eph receptors, little is known about the essential phosphorylation events that define the context and instruct cell movement. Here, we define a pathway that is required for Eph receptor B2 (EphB2)-mediated cell sorting and is conserved among multiple Eph receptors. Utilizing a HEK293 model of EphB2+/ephrinB1+ cell segregation, we found that the scaffold adaptor protein SH2 domain-containing adaptor protein B (Shb) is essential for EphB2 functionality. Further characterization revealed that Shb interacts with known modulators of cytoskeletal rearrangement and cell mobility, including Nck adaptor protein (Nck), p120-Ras GTPase-activating protein (RasGAP), and the α- and β-Chimaerin Rac GAPs. We noted that phosphorylation of Tyr297, Tyr246, and Tyr336 of Shb is required for EphB2-ephrinB1 boundary formation, as well as binding of Nck, RasGAP, and the chimaerins, respectively. Similar complexes were formed in the context of EphA4, EphA8, EphB2, and EphB4 receptor activation. These results indicate that phosphotyrosine-mediated signaling through Shb is essential in EphB2-mediated heterotypic cell segregation and suggest a conserved function for Shb downstream of multiple Eph receptors.
• Ixekizumab for the treatment of psoriasis: up-to-date

  Craig, Sarah; Warren, RB; Skin cancer and Ageing group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK (2020)

  Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinumab and Brodalumab) represent a new generation of biologic therapy with rapid and high response rates, quickly becoming a crucial part of the psoriasis treatment armamentarium.Areas covered: In this review, we describe how IL-17A antagonists disrupt inflammatory cascades in psoriasis and summarize results from clinical trials examining the safety and efficacy of ixekizumab against placebo and comparators.Expert opinion: Ixekizumab induces a 75% reduction in psoriasis area severity index (PASI 75) in 89% of patients after 12 weeks and after 1 year, PASI 75 is maintained in 80% of patients. Ixekizumab is superior to both etanercept and ustekinumab, however, further comparator trials are needed to determine superiority between newer agents. Network meta-analysis suggests that ixekizumab is one of the most rapid and efficacious agents for treating psoriasis, but ideally more long-term real-world data are needed to determine the persistence of response. Candida may be commonly encountered during treatment and IL-17 agents should be avoided in patients with inflammatory bowel disease. Overall, ixekizumab represents an efficacious and well-studied therapeutic that can offer biologic-naïve and bio-failure patients durable disease control.
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  TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

  Moukengue, B; Brown, HK; Charrier, C; Battaglia, S; Baud'huin, M; Quillard, T; Pham, TM; Pateras, IS; Gorgoulis, Vassilis G; Helleday, T; et al. (2020)

  BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.
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  Diffusion model comparison identifies distinct tumor sub-regions and tracks treatment response

  McHugh, Damien J; Lipowska-Bhalla, Grazyna; Babur, M; Watson, Y; Peset, Isabel; Mistry, Hitesh; Hubbard, Cristinacce PL; Naish, JH; Honeychurch, Jamie; Williams, KJ; et al. (2020)

  PURPOSE: MRI biomarkers of tumor response to treatment are typically obtained from parameters derived from a model applied to pre-treatment and post-treatment data. However, as tumors are spatially and temporally heterogeneous, different models may be necessary in different tumor regions, and model suitability may change over time. This work evaluates how the suitability of two diffusion-weighted (DW) MRI models varies spatially within tumors at the voxel level and in response to radiotherapy, potentially allowing inference of qualitatively different tumor microenvironments. METHODS: DW-MRI data were acquired in CT26 subcutaneous allografts before and after radiotherapy. Restricted and time-independent diffusion models were compared, with regions well-described by the former hypothesized to reflect cellular tissue, and those well-described by the latter expected to reflect necrosis or oedema. Technical and biological validation of the percentage of tissue described by the restricted diffusion microstructural model (termed %MM) was performed through simulations and histological comparison. RESULTS: Spatial and radiotherapy-related variation in model suitability was observed. %MM decreased from a mean of 64% at baseline to 44% 6 days post-radiotherapy in the treated group. %MM correlated negatively with the percentage of necrosis from histology, but overestimated it due to noise. Within MM regions, microstructural parameters were sensitive to radiotherapy-induced changes. CONCLUSIONS: There is spatial and radiotherapy-related variation in different models' suitability for describing diffusion in tumor tissue, suggesting the presence of different and changing tumor sub-regions. The biological and technical validation of the proposed %MM cancer imaging biomarker suggests it correlates with, but overestimates, the percentage of necrosis.

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