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Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa. Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging. Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).

When originally discovered, one of the initial observations was that, when all of the insulin peptide was depleted from serum, the vast majority of the insulin activity remained and this was due to a single additional peptide, IGF-II. The IGF-II gene is adjacent to the insulin gene, which is a result of gene duplication, but has evolved to be considerably more complicated. It was one of the first genes recognised to be imprinted and expressed in a parent-of-origin specific manner. The gene codes for IGF-II mRNA, but, in addition, also codes for antisense RNA, long non-coding RNA, and several micro RNA. Recent evidence suggests that each of these have important independent roles in metabolic regulation. It has also become clear that an alternatively spliced form of the insulin receptor may be the principle IGF-II receptor. These recent discoveries have important implications for metabolic disorders and also for cancer, for which there is renewed acknowledgement of the importance of metabolic reprogramming.

Dysregulation of alternative splicing is a feature of cancer, both in aetiology and progression. It occurs because of mutations in splice sites or sites that regulate splicing, or because of the altered expression and activity of splice factors and of splice factor kinases that regulate splice factor activity. Recently the CDC2-like kinases (CLKs) have attracted attention due to their increasing involvement in cancer. We measured the effect of the CLK inhibitor, the benzothiazole TG003, on two prostate cancer cell lines. TG003 reduced cell proliferation and increased apoptosis in PC3 and DU145 cells. Conversely, the overexpression of CLK1 in PC3 cells prevented TG003 from reducing cell proliferation. TG003 slowed scratch closure and reduced cell migration and invasion in a transwell assay. TG003 decisively inhibited the growth of a PC3 cell line xenograft in nude mice. We performed a transcriptomic analysis of cells treated with TG003. We report widespread and consistent changes in alternative splicing of cancer-associated genes including CENPE , ESCO2 , CKAP2 , MELK , ASPH and CD164 in both HeLa and PC3 cells. Together these findings suggest that targeting CLKs will provide novel therapeutic opportunities in prostate cancer.

This paper uses high-frequency bankside measurements from three catchments selected as part of the UK government-funded Demonstration Test Catchments (DTC) project. We compare the hydrological and hydrochemical patterns during the water year 2011–2012 from the Wylye tributary of the River Avon with mixed land use, the Blackwater tributary of the River Wensum with arable land use and the Newby Beck tributary of the River Eden with grassland land use. The beginning of the hydrological year was unusually dry and all three catchments were in states of drought. A sudden change to a wet summer occurred in April 2012 when a heavy rainfall event affected all three catchments. The year-long time series and the individual storm responses captured by in situ nutrient measurements of nitrate and phosphorus (total phosphorus and total reactive phosphorus) concentrations at each site reveal different pollutant sources and pathways operating in each catchment. Large storm-induced nutrient transfers of nitrogen and or phosphorus to each stream were recorded at all three sites during the late April rainfall event. Hysteresis loops suggested transport-limited delivery of nitrate in the Blackwater and of total phosphorus in the Wylye and Newby Beck, which was thought to be exacerbated by the dry antecedent conditions prior to the storm. The high rate of nutrient transport in each system highlights the scale of the challenges faced by environmental managers when designing mitigation measures to reduce the flux of nutrients to rivers from diffuse agricultural sources. It also highlights the scale of the challenge in adapting to future extreme weather events under a changing climate.

Bladder cancer is the tenth most common cancer and is a significant burden on health care services worldwide, as it is one of the most costly cancers to treat per patient. This expense is due to the extensive treatment and follow-ups that occur with costly and invasive procedures. Improvement in both treatment options and the quality of life these interventions offer has not progressed at the rates of other cancers, and new alternatives are desperately needed to ease the burden. A more modern approach needs to be taken, with urinary biomarkers being a positive step in making treatments more patient-friendly, but there is still a long way to go to make these widely available and of a comparable standard to the current treatment options. New targets to hit the major signalling pathways that are upregulated in bladder cancer, such as the PI3K/AkT/mTOR pathway, are urgently needed, with only one drug approved so far, Erdafitinib. Immune checkpoint inhibitors also hold promise, with both PD-1 and CDLA-4 antibody therapies approved for use. They effectively block ligand/receptor binding to block the immune checkpoint used by tumour cells. Other avenues must be explored, including drug repurposing and novel biomarkers, which have revolutionised this area in other cancers.

Accurate topographic data acquired at appropriate spatio‐temporal resolution is often the cornerstone of geomorphic research. Recent decades have seen advances in our ability to generate highly accurate topographic data, primarily through the application of remote sensing techniques. Structure from Motion‐Multi View Stereo (SfM‐MVS) and lidar have revolutionised the spatial resolution of surveys across large spatial extents. Technological developments have led to commercialisation of small form factor (SFF) 3D lidar sensors that are suited to deployment on both mobile (e.g., uncrewed aerial systems), and in fixed semi‐permanent installations. Whilst the former has been adopted, the potential for the latter to generate data suitable for geomorphic investigations has yet to be assessed. We address this gap here in the context of a 3‐month deployment where channel change is assessed in an adjusting fluvial system. We find that SFF 3D lidar sensors generate change detection products comparable to those generated using a conventional lidar system. Areas of no geomorphic change are characterised as such (mean 3D change of 0.014 m compared with 0.0014 m for the Riegl VZ‐4000), with differences in median change in eroding sections of between 0.02 and 0.04 m. We illustrate that this data enables: (a) accurate characterisation of river channel adjustments through extraction of bank long‐profiles; (b) the assessment of bank retreat patterns which help elucidate failure mechanics; and (c) the extraction of water surface elevations. The deployment of this technology will enable a better understanding of processes across a variety of geomorphic systems, as data can be captured in 4D with near real‐time processing. Plain Language Summary This research demonstrates how instruments that were initially developed for the automotive and robotics industry can be used to provide detailed information about the shape and size of landforms, and how they change over time. The instruments that we use are small, low‐cost, lidar sensors (which use laser beams to measure distances). We deployed the sensors over a 3‐month period, where they were used to assess how the banks of a river channel changed (eroded and deposited sediment). The river bank of interest was located approximately 30‐m away from the lidar sensors and we found them to generate results comparable to those obtained from conventional lidar systems. The small sensors accurately identified areas where no changes occurred, with minor differences in estimates for areas experiencing change. The fixed installation allowed for high‐resolution data to be collected every 2‐hr. Using this new technology, we were able to accurately study the change of the river channel, measure the patterns of bank retreat, understand the failure mechanisms and extract elevations of the water surface. This new technology has the potential to enhance our understanding of various environments that are undergoing change by capturing detailed data in three‐dimensional space over time. Key Points Fixed monitoring platforms using small form lidar sensors offer insight into hydrogeomorphic processes at user defined temporal resolution Change detection products are within 2–4 cm of those produced using conventional lidar systems at river bank sections Application provides quantified insight into bank retreat processes and river water levels at high spatio‐temporal resolution

The insulin-like growth factor axis is a multifaceted, complex system that comprises two ligands, IGF-I and IGF-II, receptors (IGF-1R, IGF-IIR, insulin receptor isoforms IR-A and B, and hybrid receptors) six high affinity IGF-binding proteins (IGFBPs 1–6), and IGFBP proteases [...]

The dual-function phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is the second most frequently mutated gene in human cancers. PTEN counteracts the functions of many growth factors, the most prevalent of which is insulin-like growth factor II (IGF-II). PTEN expression is stimulated by IGF-II forming a feedback loop. Investigating IGF-binding protein (IGFBP) modulation of IGF-II actions on MCF-7 breast cancer cells, we found that IGFBP-2 also regulates PTEN. The MCF-7 cells were not responsive to high doses of IGF-II due to induction of PTEN, which was not observed with an IGF-II-analog that does not bind to IGFBPs or in the presence of an inhibitor that prevents IGFs associating with IGFBPs. These cells predominantly produce IGFBP-2: blocking IGFBP-2 with a specific antibody, or preventing IGFBP-2 binding to integrins, restored the induction of PTEN and the cells were non-responsive to high doses of the IGF-II-analog. Our findings indicate that breast cancer cells do not respond to high doses of IGF-II due to induction of PTEN, but IGFBP-2, when free from IGF-II can suppress PTEN. Levels of IGFBP-2 are elevated frequently in human tumors: its ability to regulate PTEN could have important implications in relation to therapeutic strategies targeting growth factor pathways.

Background: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments. Aim: The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel. Methods: DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT–PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting. Results: The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β -1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel. Conclusion: The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.

Background The overall survival of IDH‐wildtype glioblastoma patients is poor despite best available treatments. There is an urgent need for new biomarkers to inform more precise disease stratification. Previous studies have identified insulin‐like growth factor binding protein‐2 (IGFBP‐2) as a potential biomarker for glioblastoma diagnosis and therapeutic targeting. Other studies have indicated links between the insulin‐like growth factor (IGF) axis and tumorigenic functions of a molecular chaperone glucose related protein of 78 kDa (GRP78). We aimed to interrogate the oncogenic effects of IGFBP‐2 and GRP78 in our glioma stem cell (GSC) lines and clinical cohort. Methods Immunoblotting, reverse transcription quantitative real‐time PCR were used to quantify protein and mRNA levels derived from GSCs and non‐malignant neural stem cells (NSCs). Microarray analysis was used to compare the differences in IGFBP‐2 (IGFBP‐2) and GRP78 (HSPA5) transcript expression between NSCs, GSCs and adult human cortex samples. Immunohistochemistry was used to quantify IGFBP‐2 and GRP78 expression in IDH‐wildtype glioblastoma tissue sections (n = 92) and clinical implications assessed using survival analysis. Finally, the relationship between IGFBP‐2 and GRP78 was further explored molecularly using coimmunoprecipitation. Results Here, we demonstrate that IGFBP‐2 and HSPA5 mRNA is overexpressed in GSCs and NSCs in comparison to non‐malignant brain tissue. We also determined a relationship in which G144 and G26 GSCs expressed higher IGFBP‐2 protein and mRNA than GRP78, and this was reversed in mRNA isolated from adult human cortex samples. Clinical cohort analysis revealed that Glioblastomas with high IGFBP‐2 protein expression paired with low GRP78 protein expression were significantly associated with a much shorter survival time (Median = 4 months, p = 0.019) compared with 12‐14 months for any other combination of high/low protein expression. Conclusions Inverse levels of IGFBP‐2 and GRP78 may be adverse clinical prognostic markers in IDH‐wildtype glioblastoma. Further interrogation of the mechanistic link between IGFBP‐2 and GRP78 may be important for rationalisation of their potential as biomarkers and therapeutic targets.