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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF), but have not yet been investigated in transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to evaluate tolerability, clinical outcomes, and changes in NT-proBNP levels and glomerular filtration rate (GFR) in ATTR-CM patients treated with dapagliflozin.

Patients with stable, tafamidis-treated ATTR-CM were retrospectively evaluated at the initiation of dapagliflozin and 3months thereafter. Tafamidis-treated ATTR-CM patients without SGLT2i served as a reference cohort. Overall, SLGT2i therapy was initiated in 34 patients. Seventeen patients with stable disease on tafamidis, who were subsequently started on dapagliflozin, were included in the analysis. Patients selected for SGLT2i presented with signs of advanced disease, evidenced by higher Gillmore disease stage (stage ≥2 53% vs. 27.5%; P=0.041), baseline median NT-proBNP [median (IQR) 2668pg/mL (1314-3451) vs. 1424 (810-2059); P=0.038] and loop diuretic demand (76.5% vs. 45% of patients; P=0.044), and lower LVEF (46.6±12.9 vs. 53.7±8.7%; P=0.019) and GFR (51.8±16.5 vs. 68.5±18.6mL/min; P=0.037) compared with the reference cohort. At 3-month follow-up, a numerical decrease in NT-proBNP levels was observed in 13/17 (76.5%) patients in the dapagliflozin (-190pg/mL, IQR -1,028-71, P=0.557) and 27/40 (67.5%) of patients in the control cohort (-115pg/mL, IQR -357-105, P=0.551). Other disease parameters remained stable and no adverse events occurred.

In tafamidis-treated ATTR-CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR-CM needs to be studied in randomized controlled trials.

In tafamidis-treated ATTR-CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR-CM needs to be studied in randomized controlled trials.

Surgical excision is the primary mode of treating basal cell carcinoma (BCC). Incomplete excision is a common phenomenon usually dealt with by re-excision. However, re-excision specimens often do not contain any tumor residues, rendering the procedure superfluous in hindsight. Our study objective is the identification of clinicopathological features associated with the presence of histological tumor residues in re-excision specimens.

222 patients with a total of 255 incompletely resected BCCs were enrolled in this observational case-control study. Eight clinicopathological features were correlated in a binary logistic regression analysis to the presence or absence of histological tumor residues in re-excision specimens.

Advanced age at first excision and a BCC in the high-risk zone for recurrence were found to be independent risk factors for the presence of histological tumor residues in re-excision specimens.

Our study results indicate a clear need for re-excision of incompletely resected BCCs in the aforementioned subpopulation. However, less invasive therapies such as imiquimod may be considered for the follow-up treatment of incompletely resected BCCs located in the low-risk zone for recurrence in younger patients.

Our study results indicate a clear need for re-excision of incompletely resected BCCs in the aforementioned subpopulation. However, less invasive therapies such as imiquimod may be considered for the follow-up treatment of incompletely resected BCCs located in the low-risk zone for recurrence in younger patients.Glutaminase catalyses the metabolic process called glutaminolysis. Cancer cells harness glutaminolysis to increase energy reserves under stressful conditions for rapid proliferation. Glutaminases are upregulated in many tumours. In humans, the kidney-type glutaminase (KGA) isoform is highly expressed in the kidney, brain, intestine, foetal liver, lymphocytes and in many tumours. Glutaminase inhibition is shown to be effective in controlling cancers. Previously, we and others reported the inhibition mechanism of KGA using various inhibitors that target the active and allosteric sites of the enzyme. Here, we report the identification of a novel allosteric site in KGA using the compound DDP through its complex crystal structure combined with mutational and hydrogen-deuterium exchange mass spectrometry studies. This allosteric site is located at the dimer interface, situated ~ 31 Å away from the previously identified allosteric site and ~ 32 Å away from the active site. Remarkably, the mechanism of inhibition is conserved, irrespective of which allosteric pocket is targeted, causing the same conformational changes in the key loop near the active site (Glu312-Pro329) and subsequent enzyme inactivation. Contrary to the previously identified allosteric site, the identified new allosteric site is primarily hydrophilic. This site could be effectively targeted for the synthesis of specific and potent water-soluble inhibitors of glutaminase, which will lead to the development of anticancer drugs.Cyclin-dependent kinases (CDKs), in association with cyclins, control cell cycle progression by phosphorylating a large number of substrates. In animals, activation of CDKs regularly requires both the association with a cyclin and then phosphorylation of a highly conserved threonine residue in the CDK activation loop (the classical mechanism), mediated by a CDK-activating kinase (CAK). In addition to this typical mechanism of activation, some CDKs can also be activated by the association of a cyclin to a monomeric CDK previously phosphorylated by CAK although not all CDKs can be activated by this mechanism. In animals and yeast, cyclin, in addition to being required for CDK activation, provides substrate specificity to the cyclin/CDK complex; however, in plants both the mechanisms of CDKs activation and the relevance of the CDK-associated cyclin for substrate targeting have been poorly studied. In this work, by co-expressing proteins in E. coli, we studied maize CDKA2;1a and CDKB1;1, two of the main types of CDKs that control the cell cycle in plants. These kinases could be activated by the classical mechanism and by the association of CycD2;2a to a phosphorylated intermediate in its activation loop, a previously unproven mechanism for the activation of plant CDKs. Unlike CDKA2;1a, CDKB1;1 did not require CAK for its activation, since it autophosphorylated in its activation loop. Phosphorylation of CDKB1;1 and association of CycD2;2 was not enough for its full activation as association of maize CKS, a scaffolding protein, differentially stimulated substrate phosphorylation. Our results suggest that both CDKs participate in substrate recognition.Global interest in the non-intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a diversity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10-50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether “low-dose” CBD products confer any therapeutic benefits. This is an important question to answer, as low-dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ9 -tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300-400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti-addiction effects in drug-dependent individuals. this website More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., less then 300 mg/day) oral doses of CBD.Trichodina centrostrigeata Basson, Van As et Paperna, 1983 from Oreochromis mossambicus (Peters) and O. niloticus (Linnaeus) from different host populations from Argentina, Mexico and South Africa was reviewed. Although T. centrostrigeata has a distinct denticle structure that makes morphological taxonomic inferences uncomplicated, variation of the denticles within and among individuals and populations were still observed. While traditional taxonomy of mobilines is heavily reliant on morphometrics, and recently even more so on molecular analysis, this paper proposes the use of geometric morphometry, specifically elliptical Fourier analysis, to address morphological conflicts that arise when comparing different populations. By applying this technique, combined with traditional taxonomy, it was found that T. centrostrigeata in this study can be grouped into two separate morphotypes, the first (type a) from aquaculture farms in Argentina and Mexico and the second (type b) from a natural habitat in Glen Alpine Dam, South Africa. This study supports the validity of geometric morphometry as an additional technique to distinguish not only between species but also evolutionary plasticity of the same species from different localities and habitats.Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem disorder; cardiac involvement may include eosinophilic myocarditis. A 67-year-old woman presented with 1-week history of dyspnoea and orthopnoea. She had a history of adult-onset asthma and peripheral eosinophilia. The investigations showed T-wave inversion on lateral leads, peripheral eosinophilia, elevated troponin and BNP values, and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. Computed tomography excluded coronary disease and showed bilateral basal ground-glass opacities, air-space consolidation, and bilateral reticular-nodular pattern. Cardiac magnetic resonance findings were compatible with active myocardial inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of eosinophilic myocarditis, and a therapy with oral corticosteroids and heart failure medications was started.Schizophrenia is a mental illness affecting the normal lifestyle of adults and early adolescents incurring major symptoms as jumbled speech, involvement in everyday activities eventually got reduced, patients always struggle with attention and memory, reason being both the genetic and environmental factors responsible for altered brain chemistry and structure, resulting in schizophrenia and associated orphan diseases. The network biology describes the interactions among genes/proteins encoding molecular mechanisms of biological processes, development, and diseases. Besides, all the molecular networks, protein-protein Interaction Networks have been significant in distinguishing the pathogenesis of diseases and thereby drug discovery. The present meta-analysis prioritizes novel disease indications viz. rare and orphan diseases associated with target Glutamate Ionotropic Receptor NMDA Type Subunit 1, GRIN1 using text mining knowledge-based tools. Furthermore, ZINC database was virtually screened, and binding conformation of selected compounds was performed and resulted in the identification of Narciclasine (ZINC04097652) and Alvespimycin (ZINC73138787) as potential inhibitors.