Four selected commercial seaweeds: biologically active compounds, antioxidant and cytotoxic properties

The aim of this research work was to study the chemical characterisation, antioxidant and cytotoxic activity of ethanolic extracts of four commercial algae species Arame, Kombu, Hijiki and Wakame. The highest scavenging activity has been observed in Arame extract. Antioxidant potential of all extracts was in correlation with total phenol content (Arame extract: 319.15 + - 0,56 mg GAE/g. d.w) and it was not in correlation with total carotenoids content (Wakame: 75.15 + - 0.20 mg/g). Polyphenols were quantified using LC-MS/MS technique. Baicalein and amentoflavone were identified in higher amount in relation to other phenols. Intracellular antioxidant activity and cytotoxicity of algae extracts were evaluated on the human prostate cancer cell line PC3. Although presented biomolecules in the extracts have demonstrated in vitro antioxidant activity, they did not show a significant effect on PC3 cells. However, this study opens up a broad perspective for the further comprehensive investigaton of these, commercial, sea weed's biopotential

Mechanism of action of novel NO-releasing furoxan derivatives of aspirin in human platelets

1 Incorporation of a nitric oxide (NO)-releasing moiety in aspirin can overcome its gastric side effects. 2 We investigated the NO-release patterns and antiplatelet effects of novel furoxan derivatives of aspirin (B8 and B7) in comparison to existing antiplatelet agents. 3 Cyclooxygenase (COX) activity was investigated in purified enzyme using an electron paramagnetic resonance-based technique. Concentration–response curves for antiplatelet agents±the soluble guanylate cyclase inhibitor, ODQ (50 μM) were generated in platelet-rich plasma (PRP) and washed platelets (WP) activated with collagen using turbidometric aggregometry. NO was detected using an isolated NO electrode. 4 The furoxan derivatives of aspirin (B8, B7) and their NO-free furazan equivalents (B16, B15; all 100 μM) significantly inhibited COX activity (P<0.01; n=6) in vitro and caused aspirin-independent, cGMP-dependent inhibition of collagen-induced platelet aggregation in WP. B8 was more potent than B7 (PRP IC50=0.62±0.1 μM for B8; 400±89 μM for B7; P<0.0001. WP IC50s=0.6±0.1 and 62±10 μM, respectively). The NO-free furazan counterparts were less potent antiplatelet agents (WP IC50s=54±3 μM and 62±10 μM, respectively; P<0.0001, B8 vs B16). Of the hybrids investigated, only B8 retained antiplatelet activity in PRP. 5 NO release from furoxan–aspirin hybrids was undetectable in buffer alone, but was accelerated in the presence of either plasma or plasma components, albumin (4%), glutathione (GSH; 3 μM) and ascorbate (50 μM), the effects of which were additive for B7 but not B8. NO generation from furoxans was greatly enhanced by platelet extract, an effect that could largely be explained by the synergistic effect of intracellular concentrations of GSH (3 mM) and ascorbate (1 mM). 6 We conclude that the decomposition of furoxan–aspirin hybrids to generate biologically active NO is catalysed by endogenous agents which may instil a potential for primarily intracellular delivery of NO. The blunting of the aspirin effects of furoxan hybrids is likely to be due to loss of the acetyl moiety in plasma; the observed antiplatelet effects are thereby primarily mediated via NO release. Compounds of this class might represent a novel means of inhibiting platelet aggregation by a combination of NO generation and COX inhibition

Systematic review of dexketoprofen in acute and chronic pain

Background: Dexketoprofen, and NSAID used in the management of acute and chronic pains, is licensed in several countries but has not previously been the subject of a systematic review. We used published and unpublished information from randomised clinical trials (RCTs) of dexketoprofen in painful conditions to assess evidence on efficacy and harm. Methods: PubMed and Cochrane Central were searched for RCTs of dexketoprofen for pain of any aetiology. Reference lists of retrieved articles and reviews were also searched. Menarini Group produced copies of published and unpublished studies (clinical trial reports). Data were abstracted into a standard form. For studies reporting results of single does administration, the number of patients with at least 50% pain relief was derived and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief compared with placebo. Results: Thirty-five trials were found in acute pain and chronic pain; 6,380 patients were included, 3, 381 receiving dexketoprofen. Information from 16 trials (almost half the total patients) was obtained from clinical trial reports from previously unpublished trials or abstracts. Almost all of the trials were of short duration in acute conditions or recent onset pain. All 12 randomised trials that compared dexketoprofen (any dose) with placebo found dexketoprofen to be statistically superior. Five trials in postoperative pain yielded NNTs for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). In 29/30 active comparator trials, dexketoprofen at the dose used was at least equivalent in efficacy to comparator drugs. Adverse event withdrawal rates were low in postoperative pain and somewhat higher in trials of longer duration; no serious adverse events were reported. Conclusion: Dexketoprofen was at least as effective as other NSAIDs and paracetamol/opioid combinations. While adverse event withdrawal was not different between dexketoprofen and comparator analgesics, the different conditions and comparators studies precluded any formal analysis. Exposure was limited, and no conclusions could be drawn about safety in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events

Systematic review of methods used in meta-analyses where a primary outcome is an adverse or unintended event

addresses: Peninsula College of Medicine and Dentistry, St Luke's Campus, University of Exeter, Exeter, UK. [email protected]: PMCID: PMC3528446types: Journal Article; Research Support, Non-U.S. Gov't© 2012 Warren et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Adverse consequences of medical interventions are a source of concern, but clinical trials may lack power to detect elevated rates of such events, while observational studies have inherent limitations. Meta-analysis allows the combination of individual studies, which can increase power and provide stronger evidence relating to adverse events. However, meta-analysis of adverse events has associated methodological challenges. The aim of this study was to systematically identify and review the methodology used in meta-analyses where a primary outcome is an adverse or unintended event, following a therapeutic intervention

The Relationship Between Shoulder Range of Motion and Arm Stress in College Pitchers: A MOTUS Baseball Study

The Relationship Between Shoulder Range of Motion and Arm Stress in College Pitchers: A MOTUS Baseball Study Abstract Predictors of Elbow Torque Among College Baseball Pitchers Purpose: To investigate the relationship of shoulder range of motion (ROM) conditions, such as glenohumeral internal rotation deficiency (GIRD) and external rotation gain (ERG), to torque across the medial elbow in college pitchers. Methods: Pitchers were recruited from three local college baseball teams. Exclusion criteria included injury or restricted activity due to pain. They were evaluated within two weeks before their first game of the season. Pitchers completed an intake survey at the time of shoulder ROM and upper extremity length measurements. Pitchers were fitted with a MOTUS sensor baseball sleeve (Motus Global, Massapequa, NY). The sensor placed at the medial elbow reported elbow torque, arm speed, arm slot, and shoulder rotation for each pitch, while a radar gun measured peak ball velocity. After adequate warmup, pitchers threw 5 fastballs in a standardized manner off the mound at game-speed effort. The primary outcome was to evaluate the relationship between shoulder ROM and medial elbow torque. Additional outcomes evaluated pitcher characteristics, demographics, and outcome scores in the context of shoulder ROM. Outcomes were assessed via a multivariable model, which controlled for possible covariates. Results: Twenty-eight pitchers were included in the preseason analysis with an average (SD) age of 20.1 (1.3) years and playing experience of 15.3 (1.8) years, 2.5 (1.2) of those years at collegiate level. The dominant shoulder demonstrated decreased internal rotation (54.5+/-10.6 vs 65.8+/-9.1) and increased external rotation (ER, 94.1+/-10.4 vs 88.4+/-9.2) relative to the non-dominant side (p \u3c 0.001), while total rotational range of motion (TRROM) was significantly decreased in the dominant arm (148.6+/-12.4 vs 154.1+/-10.6, p \u3c 0.001). The average GIRD was 11.3 (9.87) and average ERG was 4.4 (8.87). External rotation was found to be a predictor of arm stress, with an increase in 0.35 Nm of elbow torque for every degree increase in ER (beta = 0.35+/-0.06, p = 0.003); there was moderate correlation between ER and arm stress (r = .45, P\u3c.001). Pitchers demonstrated significantly greater arm stress with the following shoulder ROM measurements: GIRD \u3c 20 as compared to greater than 20 degrees (46.6 +/- 0.5 versus 43.5 +/- 1.1, P=.011), ERG \u3e 5 as compared to \u3c 5 degrees (47.4 +/- 0.7 versus 45.1 +/- 0.6, P=.014), and loss of total rotational ROM \u3c 5 as compared to \u3e 5 degrees (46.6 +/- 0.5 versus 43.6 +/- 1.1, P=.013). Conclusions: College pitchers with external rotation gain produced greater medial elbow torque during the pitching movement. These findings indicate that pitchers with increased external rotation of their throwing arm may experience greater elbow stress while pitching, placing their medial elbow at risk of injury. Level of Evidence: Level II prospective observational study Key Words: UCL, Ulnar Collateral Ligament, Pitching, Tommy John, Laxity, Pain, Elbow, Injur

LiFT: A Scalable Framework for Measuring Fairness in ML Applications

Many internet applications are powered by machine learned models, which are usually trained on labeled datasets obtained through either implicit / explicit user feedback signals or human judgments. Since societal biases may be present in the generation of such datasets, it is possible for the trained models to be biased, thereby resulting in potential discrimination and harms for disadvantaged groups. Motivated by the need for understanding and addressing algorithmic bias in web-scale ML systems and the limitations of existing fairness toolkits, we present the LinkedIn Fairness Toolkit (LiFT), a framework for scalable computation of fairness metrics as part of large ML systems. We highlight the key requirements in deployed settings, and present the design of our fairness measurement system. We discuss the challenges encountered in incorporating fairness tools in practice and the lessons learned during deployment at LinkedIn. Finally, we provide open problems based on practical experience.Comment: Accepted for publication in CIKM 202

1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM

Foundational Challenges in Assuring Alignment and Safety of Large Language Models

\ua9 2024, Transactions on Machine Learning Research. All rights reserved. This work identifies 18 foundational challenges in assuring the alignment and safety of large language models (LLMs). These challenges are organized into three different categories: scientific understanding of LLMs, development and deployment methods, and sociotechnical challenges. Based on the identified challenges, we pose 200+ concrete research questions