Reedmunro1736

The serine/threonine kinase AKT is a key component of the PI3K/AKT/mTOR signaling pathway as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Deregulation of this pathway is a common event in breast cancer including hormone receptor-positive (HR+) disease, HER2-amplified, and triple negative tumors. Hence, targeting AKT represents an attractive treatment option for many breast cancer subtypes, especially those resistant to conventional treatments. Several AKT inhibitors have been recently developed and two ATP-competitive compounds, capivasertib and ipatasertib, have been extensively tested in phase I and II clinical trials either alone, with chemotherapy, or with hormonal agents. Additionally, phase III trials of capivasertib and ipatasertib are already under way in HR+ and triple-negative breast cancer. While the identification of predictive biomarkers of response and resistance to AKT inhibition represents an unmet need, new combination strategies are under investigation aiming to boost the therapeutic efficacy of these drugs. As such, trials combining capivasertib and ipatasertib with CDK4/6 inhibitors, immune checkpoint inhibitors, and PARP inhibitors are currently ongoing. This review summarizes the available evidence on AKT inhibition in breast cancer, reporting both efficacy and toxicity data from clinical trials along with the available translational correlates and then focusing on the potential use of these drugs in new combination strategies.Background Pulmonary Fibrosis (PF) is an interstitial lung disease characterized by excessive accumulation of extracellular matrix in the lungs, which disrupts the structure and gas exchange of the alveoli. There are only two approved therapies for PF, nintedanib (Nib) and pirfenidone. Therefore, the use of Chinese medicine for PF is attracting attention. Tianlongkechuanling (TL) is an effective Chinese formula that has been applied clinically to alleviate PF, which can enhance lung function and quality of life. see more Purpose The potential effects and specific mechanisms of TL have not been fully explored, yet. In the present study, proteomics was performed to explore the therapeutic protein targets of TL on Bleomycin (BLM)-induced Pulmonary Fibrosis. Method BLM-induced PF mice models were established. Hematoxylineosin staining and Masson staining were used to analyze histopathological changes and collagen deposition. To screen the differential proteins expression between the Control, BLM, BLM + TL and BLM + Nib (By-phosphate synthase (CPS1), argininosuccinate synthase (ASS1), ornithine aminotransferase (OAT) argininosuccinate lyase (ASL) and inducible nitric oxide synthase (iNOS) was significantly decreased after TL treatments. Conclusion Administration of TL in BLM-induced mice resulted in decreasing pulmonary fibrosis. Our findings propose that the down regulation of arginase-ornithine pathway expression with the reduction of arginase biosynthesis is a central mechanism and potential treatment for pulmonary fibrosis with the prevention of TL.Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p less then 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) comparmacogenetics does not justify its inclusion in pharmacogenetic guidelines.Background Pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAH-CHD) occurs predominantly among patients with uncorrected congenital heart disease (CHD). It is an intractable problem to control PAH continuously and stably after an operation. Methods 1) OPLS-DA combined with S-plot was used to retrospectively analyze the results of preoperative and postoperative PAH and 39 biochemical indicators of 235 patients admitted to Fuwai Yunnan Cardiovascular Hospital from January 2019 to December 2020. 2) Combined with Meta-analysis, the recurrence in postoperative PAH was analyzed in terms of operation factors, doses administered, and age factors. Results 1) 4 indicators (PAH, RBC, HGB, and CO2) that reflect the prognosis of patients had been found by OPLS-DA combined with S-plot. 2) The recurrence rate of postoperative PAH was 37.02%. The comprehensive therapeutic effect of interventional closure was better than that of surgical operation. PAH was not significantly higher again in patients who received either the instruction dose or the literature dose. Postoperative combination therapy (bosentan and sildenafil) was more effective than bosentan alone. Recovery after treatment was better in infants than in the other four age groups. Conclusion OPLS-DA combined with S-plot was used for the first time to analyze clinical examination data. In this study, this method proved to be a feasible method for analyzing clinical data We recommend interventional closure as the first choice for patients with PAH-CHD. For postoperative oral therapy, we recommend the combination therapy (bosentan with sildenafil). To prevent the recurrence, the dose should be strictly prescribed according to the instructions, literature, or body surface area converted. Moreover, we recommend treatment at a young age in these patients.Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the ABCG2 and ABCB1 genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for ABCG2 and ABCB1, and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to ABCG2 (c.421C>A and c.34G>A) and ABCB1 (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups ( less then 80 mg/dl); subjects with high plasma AGP levels (n = 5, ≥80 mg/dl) were excluded. The results indicate that plasma AGP levels and ABCG2 polymorphisms modulated imatinib pharmacokinetics; however, the effects of the ABCG2 transporter was masked at high plasma AGP levels.Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most widely used classes of drugs and play a pivotal role in the therapy of numerous inflammatory diseases. However, the adverse effects of these drugs, especially when applied chronically, frequently affect gastrointestinal (GI) tract, resulting in ulceration and bleeding, which constitutes a significant limitation in clinical practice. On the other hand, it has been recently discovered that gaseous mediators nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) contribute to many physiological processes in the GI tract, including the maintenance of GI mucosal barrier integrity. Therefore, based on the possible therapeutic properties of NO, H2S and CO, a novel NSAIDs with ability to release one or more of those gaseous messengers have been synthesized. Until now, both preclinical and clinical studies have shown promising effects with respect to the anti-inflammatory potency as well as GI-safety of these novel NSAIDs. This review provides an overview of the gaseous mediators-based NSAIDs along with their mechanisms of action, with special emphasis on possible implications for GI mucosal defense mechanisms.Purpose To evaluate the effect of repeated intravitreal bevacizumab injections on blood-aqueous barrier permeability in eyes with neovascular age-related macular degeneration (AMD). Patients and Methods Forty-eight consecutive patients with neovascular AMD received 3 intravitreal bevacizumab injections (1 mg) every 30-40 days. Subjects were followed for a period of 4 months and were examined at baseline, 1 day and 1 month after each injection. A control group comprised of 19 neovascular AMD patients waiting to begin anti-vascular endothelial growth factor (VEGF) therapy. Anterior chamber (AC) inflammation was evaluated with biomicroscopy and laser flare photometry. Results None of the subjects treated with bevacizumab had detectable ocular inflammation during follow-up. An analysis for variance (ANOVA) of the mixed-effects model has shown neither an effect between treatment and control group (p = 0.921), nor over the time course of the follow-up (p = 0.773). Before treatment, median AC inflammation was 6.7 photons/ms (range 3.5-18.2 photons/ms). One month after the first, second, and third injections, median laser flare was 6.4, 6.8, and 6.6 photons/ms, respectively, none of which were significantly different from baseline (all p > 0.05). Blood-aqueous barrier permeability did not change between injections and was not different from the control group. Conclusion Inflammation induced by intravitreal bevacizumab was not detected by examination or flare photometry. This suggests that monthly bevacizumab dosing seems to be safe. The absence of AC inflammation could also reflect the known anti-inflammatory properties of anti-VEGF agents.Background The outbreak of the pandemic coronavirus disease 2019 (COVID-19) has now become a global pandemic spreading throughout the world. Unfortunately, due to the high infectiousness of the novel β-coronavirus, it is very likely to become an ordinary epidemic. The development of dietary supplements and functional foods might provide a strategy for the prevention and management of COVID-19. Scope and Approach A great diversity of potential edible and medicinal plants and/or natural compounds showed potential benefits in managing SARS, which may also combat COVID-19. Moreover, many plants and compounds have currently been proposed to be protective against COVID-19. This information is based on data-driven approaches and computational chemical biology techniques. In this study, we review promising candidates of edible and medicinal plants for the prevention and management of COVID-19. We primarily focus on analyzing their underlying mechanisms. We aim to identify dietary supplements and functional foods that assist in managing this epidemic. Key findings and Conclusion We infer that acetoside, glyasperin, isorhamnetin, and several flavonoid compounds may prevent and/or be effective in managing COVID-19 by targeting the viral infection, reducing the host cytokine storm, regulating the immune response, and providing organ protection. These bioactive dietary components (used either alone or in combination) might assist in the development of dietary supplements or functional foods for managing COVID-19.