Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

Published online: 6 September 2023BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.Josephine A. Hinneh, Joanna L. Gillis, Chui Yan Mah, Swati Irani, Raj K. Shrestha, Natalie K. Ryan, Enomoto Atsushi, Zeyad D. Nassar, David J. Lynn, Luke A. Selth, Masashi Kato, Margaret M. Centenera and Lisa M. Butle

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis

Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.Zeyad D Nassar, Chui Yan Mah, Jonas Dehairs, Ingrid JG Burvenich ... Lisa M Butler ... Luke Selth ... et al

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Large-scale IPM validation in Basmati rice (Oryza sativa) in Western Uttar Pradesh, India

Work involved the synthesis and validation of IPM in basmati rice in farmers' participatory mode at Bamabwad (Gautam Budh Nagar, UP). Module has been successfully implemented at Bambawad with significant reduction chemical pesticide application and higher benefit-cost ratio.Pusa Basmati 1121, a high-yielding aromatic rice (Oryza sativa L.) variety released by ICAR-IARI in 2005, became widely popular among farmers of Punjab, Western Uttar Pradesh and Haryana in India due to higher yield and good price in the market. But, soon after its release, the variety was severely affected by bakanae foot rot disease (Fusarium fujikuroi). The ICAR-National Research Centre for Integrated Pest Management (NCIPM) synthesized an integrated pest management (IPM) module and validated it in large-scale at Bambawad village (District Gautam Budh Nagar, UP) in farmers’ participatory mode during 2010-14. The trial was initiated on 40 ha in 2010, which was gradually increased to 80, 120, 200 and 286 ha during 2011, 2012, 2013 and 2014, respectively. The IPM module involved green manuring, seed treatment with carbendazim, seedling root dipping in Pseudomonas fluorescens, pest monitoring and need-based application of bioagents/ pesticides. Implementation of the module resulted in a significant reduction in the incidence of bakanae ranging from 0.05±0.01 to 10.18±4.05% in IPM fields against 1.22±0.27 to 46.5±6.30% in Farmers’ practices (FP). Brown plant hopper (Nilaparvata lugens) population (average of the season) remained 7.74, 9.55, 1.22, 4.32 and 0.49 nymphs and adults/hill in IPM against 31.13, 14.16, 1.36, 7.24 and 0.82 in FP fields during 2010, 2011, 2012, 2013 and 2014, respectively. Regular pest monitoring and ETL-based application of pesticides in IPM helped in conservation of spider population in IPM as compared to FP with very low application of chemical pesticides, i.e. 103.2 g a.i./ha in IPM against 1214.4 g a.i./ha in FP. Analysis of rice grain samples for pesticide residue indicated carbendazim below detectable level. IPM trial also resulted in higher yield (36.01 q/ha in IPM against 26.24 q/ha in FP) and benefit- cost ratio (3.80 in IPM and 2.56 in FP) as compared to FP (Average of five years).ICAR-NCIP

On the motion and appearance of specularities in image sequences

Abstract. Real scenes are full of specularities (highlights and reflections), and yet most vision algorithms ignore them. In order to capture the appearance of realistic scenes, we need to model specularities as separate layers. In this paper, we study the behavior of specularities in static scenes as the camera moves, and describe their dependence on varying surface geometry, orientation, and scene point and camera locations. For a rectilinear camera motion with constant velocity, we study how the specular motion deviates from a straight trajectory (disparity deviation) and how much it violates the epipolar constraint (epipolar deviation). Surprisingly, for surfaces that are convex or not highly undulating, these deviations are usually quite small. We also study the appearance of specularities, i.e., how they interact with the body reflection, and with the usual occlusion ordering constraints applicable to diffuse opaque layers. We present a taxonomy of specularities based on their photometric properties as a guide for designing separation techniques. Finally, we propose a technique to extract specularities as a separate layer, and demonstrate it using an image sequence of a complex scene.

Algorithms for Scalable Storage Servers

We survey a set of algorithmic techniques that make it possible to build a high performance storage server from a network of cheap components. Such a storage server oers a very simple programming model. To the clients it looks like a single very large disk that can handle many requests in parallel with minimal interference between the requests