Phosphorus bioavailability in soil profiles of a long-term fertilizer experiment: The evaluation of their bioaccessibility

Global agricultural productivity depends on the use of finite phosphorus (P) resources of which not only the topsoil, but also subsoil, can hold immense reserves. To assess potential soil contribution to plant nutrition, we compared the P status of Stagnic Cambisol profiles in experimental plots that received different P fertilizer applications (control, triple superphosphate (TSP), compost, compost+TSP) for 16 years. Sequential fractionation was combined with P K-edge X-ray absorption near edge structure (XANES) spectroscopy to identify the chemical P speciation. Fertilized topsoils (21 to 69 kg P ha-1 a-1) showed P reserves larger by a factor of 1.2 to 1.4, and subsoil P reserves larger by a factor of 1.3 to 1.5 than those of the control. P-XANES revealed the predominance of inorganic P species such as moderately labile Fe- (46 to 92%), Al- (0 to 40%), and Ca- (0 to 15%) P compounds besides organic P (0 to 13%) in all treatments. The fertilizer application slightly altered P speciation throughout the profiles, but the type of fertilizer had no significant effect on it. Optimal plant growth requirements are restricted by the exchangeable P from the solid phase within the soil solution. Therefore, ongoing research focuses on the accessibility of P from P loaded amorphous Fe- and Al-hydroxides, previously identified as the predominant abiotic P forms. To assess their P desorption potential, P-33 rhizotron experiments combined with P-33 isotopic exchange kinetics (IEK) are underway. Preliminary results indicated that besides differences in P binding capacity of soil hydroxides, physical soil parameters, such as the matric potential, strongly control soil P availability, thus plant P acquisition rates can vary among different soil types. Our results gained new detailed information about P bioavailability under agricultural practice. The investigations towards P bioaccessibility may contribute to improved interpretation of soil P tests and reduced fertilizer recommendations

A Simplified, Sequential, Phosphorus Fractionation Method

Hedley et al. (1982) developed what has become the most widely used (and modified), phosphorus (P) fractionation technique. It consists of sequential extraction of increasingly less phytoavailable P pools. Extracts are centrifuged at up to 25000 g (RCF) and filtered to 0.45 μm to ensure that soil is not lost between extractions. In attempting to transfer this method to laboratories with limited facilities, it was considered that access to high-speed centrifuges, and the cost of frequent filtration may prevent adoption of this P fractionation technique. The modified method presented here was developed to simplify methodology, reduce cost, and therefore increase accessibility of P fractionation technology. It provides quantitative recovery of soil between extractions, using low speed centrifugation without filtration. This is achieved by increasing the ionic strength of dilute extracts, through the addition of NaCl, to flocculate clay particles. Addition of NaCl does not change the amount of P extracted. Flocculation with low speed centrifugation produced extracts comparable with those having undergone filtration (0.025 μm). A malachite green colorimetric method was adopted for inorganic P determination, as this simple manual method provides high sensitivity with negligible interference from other anions. This approach can also be used for total P following digestion, alternatively non-discriminatory methods, such as inductively coupled plasma atomic emission spectroscopy, may be employed

The stability of the deadlift three repetition maximum

This study investigated the stability of three repetition maximum (3RM) strength during the deadlift. Eleven participants performed four testing sessions comprising a one repetition maximum test and 3RM tests separated by 48 h. Preparedness was assessed before each testing session using countermovement jumps and by measuring barbell velocity during each set of deadlifts. Trivial statistically significant differences were determined for the 3RM between T1 and both T2 ( p = 0.012; ES [95% CI] = −0.1 [−0.58, 0.41]) and T3 ( p = 0.027; ES [95% CI] = −0.09 [−0.57, −0.43]). No significant differences were noted between T2 and T3 ( p = 0.595; ES [95% CI] = 0.01 [−0.49, 0.50]). No significant differences in jump height ( p = 0.071), time-to-take-off ( p = 0.862), eccentric displacement ( p = 0.209), or mean force during any countermovement jump sub-phase were found between each session ( p = 0.529–0.913). Small differences in barbell mean velocity were found between both T1–T2 (effect size statistics (ES) = −0.21–0.27) and T2–T3 (ES = 0.31–0.48), while trivial differences were found at others. Therefore, 3RM deadlift strength appears stable enough over a microcycle to continue using traditionally recommended heavy/light programming strategies

Changes in deadlift six repetition maximum, countermovement jump performance, barbell velocity, and perceived exertion over the duration of a microcycle

The primary aim of this study was to investigate the stability of the six-repetition maximum (6RM) deadlift over the length of a five-day microcycle and whether the fatigue induced by maximal effort testing detrimentally impacted preparedness. Twelve participants performed four testing sessions, comprising a one-repetition maximum test and three 6RM tests separated by 48 hours. Countermovement jumps were performed before each testing session, and barbell velocity was measured during each warm-up set to assess changes in preparedness. The 6RM deadlift was not statistically different between any of the testing sessions ( p = .056; ηp2 = 0.251). Similarly, there were no significant differences in jump height or other CMJ variables between sessions ( p > .05). There were small to moderate differences in mean barbell velocity between the first and second 6RM test ( g = 0.24–0.88), while there were only small differences in mean velocity (MV) between the second and third 6RM test at some of the warm-up loads (40% 6RM: g = 0.20; 80% 6RM: g = −0.47). Taken collectively, these data indicate that 6RM deadlift strength is stable over five days and does not appear to induce sufficient fatigue to impact vertical jump performance or rating of perceived exertion despite some changes in barbell velocity

Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom

\ua9 The Author(s) 2024.Background: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. Methods: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. Results: 132 pts were included. Median age was 56 years (28–91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5–6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. Conclusion: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience

ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response.

Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients

Characterisation of bioenergetic pathways and related regulators by multiple assays in human tumour cells

Background: Alterations in cellular metabolism are considered as hallmarks of cancers, however, to recognize these alterations and understand their mechanisms appropriate techniques are required. Our hypothesis was to determine whether dominant bioenergetic mechanism may be estimated by comparing the substrate utilisation with different methods to detect the labelled carbon incorporation and their application in tumour cells. Methods: To define the bioenergetic pathways different metabolic tests were applied: (a) measuring CO2 production from [1-14C]-glucose and [1-14C]-acetate; (b) studying the effect of glucose and acetate on adenylate energy charge; (c) analysing glycolytic and TCA cycle metabolites and the number of incorporated 13C atoms after [U-13C]-glucose/[2-13C]-acetate labelling. Based on [1-14C]-substrate oxidation two selected cell lines out of seven were analysed in details, in which the highest difference was detected at their substrate utilization. To elucidate the relevance of metabolic characterisation the expression of certain regulatory factors, bioenergetic enzymes, mammalian target of rapamycin (mTOR) complexes (C1/C2) and related targets as important elements at the crossroad of cellular signalling network were also investigated. Results: Both [U-13C]-glucose and [1-14C]-substrate labelling indicated high glycolytic capacity of tumour cells. However, the ratio of certain 13C-labelled metabolites showed detailed metabolic differences in the two selected cell lines in further characterisation. The detected differences of GAPDH, β-F1-ATP-ase expression and adenylate energy charge in HT-1080 and ZR-75.1 tumour cells also confirmed the altered metabolism. Moreover, the highly limited labelling of citrate by [2-13C]-acetate-representing a novel functional test in malignant cells-confirmed the defect of TCA cycle of HT-1080 in contrast to ZR-75.1 cells. Noteworthy, the impaired TCA cycle in HT-1080 cells were associated with high mTORC1 activity, negligible protein level and activity of mTORC2, high expression of interleukin-1β, interleukin-6 and heme oxygenase-1 which may contribute to the compensatory mechanism of TCA deficiency. Conclusions: The applied methods of energy substrate utilisation and other measurements represent simple assay system using 13C-acetate and glucose to recognize dominant bioenergetic pathways in tumour cells. These may offer a possibility to characterise metabolic subtypes of human tumours and provide guidelines to find biomarkers for prediction and development of new metabolism related targets in personalized therapy. © 2016 Jeney et al

SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.

SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel–irinotecan as first-line therapy for ovarian cancer

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m−2 (arm A, n=51) or docetaxel 60 mg m−2 with irinotecan 200 mg m−2 (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58–81%; P=0.079; arm B 67% (90% CI 55–78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3–4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3–4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted

Regional adaptation defines sensitivity to future ocean acidification

Physiological responses to temperature are known to be a major determinant of species distributions and can dictate the sensitivity of populations to global warming. In contrast, little is known about how other major global change drivers, such as ocean acidification (OA), will shape species distributions in the future. Here, by integrating population genetics with experimental data for growth and mineralization, physiology and metabolomics, we demonstrate that the sensitivity of populations of the gastropod Littorina littorea to future OA is shaped by regional adaptation. Individuals from populations towards the edges of the natural latitudinal range in the Northeast Atlantic exhibit greater shell dissolution and the inability to upregulate their metabolism when exposed to low pH, thus appearing most sensitive to low seawater pH. Our results suggest that future levels of OA could mediate temperature-driven shifts in species distributions, thereby influencing future biogeography and the functioning of marine ecosystems