Breastfeeding undoubtedly provides important benefits to the mother-infant dyad and should be encouraged. Mastitis, one of the common but major cause of premature weaning among lactating women, is an ...inflammation of connective tissue within the mammary gland. This study reports the influence of mastitis on human milk microbiota by utilizing 16 S rRNA gene sequencing approach. We sampled and sequenced microbiome from 50 human milk samples, including 16 subacute mastitis (SAM), 16 acute mastitis (AM) and 18 healthy-controls. Compared to controls, SAM and AM microbiota were quite distinct and drastically reduced. Genera including, Aeromonas, Staphylococcus, Ralstonia, Klebsiella, Serratia, Enterococcus and Pseudomonas were significantly enriched in SAM and AM samples, while Acinetobacter, Ruminococcus, Clostridium, Faecalibacterium and Eubacterium were consistently depleted. Further analysis of our samples revealed positive aerotolerant odds ratio, indicating dramatic depletion of obligate anaerobes and enrichment of aerotolerant bacteria during the course of mastitis. In addition, predicted functional metagenomics identified several gene pathways related to bacterial proliferation and colonization (e.g. two-component system, bacterial secretion system and motility proteins) in SAM and AM samples. In conclusion, our study confirmed previous hypothesis that mastitis women have lower microbial diversity, increased abundance of opportunistic pathogens and depletion of commensal obligate anaerobes.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
CDK4/6 inhibitors significantly prolong progression-free survival in patients with advanced hormone receptor-positive (HR+) HER2-negative breast cancer. Despite recent successes, patients acquire ...resistance, necessitating the development of additional novel therapeutic strategies. Bromodomain and extra-terminal domain (BET) proteins are key epigenetic regulators that interact with acetylated lysine (AcLys) residues of histones or transcription factors. BET proteins are directly involved in modulating estrogen receptor (ER) signaling and the cell cycle. Therefore, BET inhibitors can potentially offer new strategies in the treatment of advanced ER+ breast cancer. ZEN-3694 is an orally bioavailable small molecule BET inhibitor currently being evaluated in Phase 1/2 clinical trials (NCT03901469). To assess a potential combination strategy in a CDK4/6i resistant breast cancer population, we investigated the mechanism of action of ZEN-3694 combined with CDK4/6 inhibitors in the ER+ cell lines resistant to palbociclib or abemaciclib. Here, we describe that the combination of ZEN-3694 with CDK4/6i potently inhibits proliferation and induces apoptosis in CDK4/6i resistant cell lines. The resistance to both palbociclib and abemaciclib was associated with the strong upregulation of CDK6 and CCND1 protein levels, which was reversed by the ZEN-3694 treatment. Furthermore, RNAseq data and pathway analysis elucidated the combinatorial effects of ZEN-3694 with CDK4/6 inhibitors through significant downregulation of multiple pathways involved in cell cycle regulation, cellular growth, proliferation, apoptosis, inflammation, and cellular immune response. Our data indicate that ZEN-3694 has therapeutic potential in combination with CDK4/6 inhibitors in patients with advanced ER+ breast resistant to CDK4/6 inhibitors.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction ...which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles. We report that RVX-297 preferentially binds to the BD2 domains of the BET bromodomain and Extra Terminal (BET) family of protein. We demonstrate the differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography, and describe the structural differences driving the BD2 selective binding of RVX-297. The isothermal titration calorimetry (ITC) data illustrate the related differential thermodynamics of binding of RVX-297 to single as well as dual BET bromodomains.
Display omitted
•A novel inhibitor of BET bromodomains, RVX-297 is described.•The differential binding modes of RVX-297 in BD1 and BD2 domains of BRD4 and BRD2 using X-ray crystallography are described.•RVX-297 preferentially binds to the BD2 domains of the BET bromodomains.•The structural and thermodynamic properties of the BD2 selective binding of RVX-297 are characterized.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract High density lipoproteins (HDL), through activity of the main protein component apolipoprotein A-I (ApoA-I), can reduce the risk of cardiovascular disease (CVD) by removing excess ...cholesterol from atherosclerotic plaque. In this study, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor RVX-208 increases ApoA-I gene transcription and protein production in human and primate primary hepatocytes. Accordingly, RVX-208 also significantly increases levels of ApoA-I, HDL-associated cholesterol, and HDL particle number in patients who received the compound in recently completed phase 2b trials SUSTAIN and ASSURE. Moreover, a post-hoc analysis showed lower instances of major adverse cardiac events in patients receiving RVX-208. To understand the effects of RVX-208 on biological processes underlying cardiovascular risk, we performed microarray analyses of human primary hepatocytes and whole blood treated ex vivo. Overall, data showed that RVX-208 raises ApoA-I/HDL and represses pro-inflammatory, pro-atherosclerotic and pro-thrombotic pathways that can contribute to CVD risk.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
A new series of indole-oxindole clubbed 1,2,3-triazole hybrids 5(a–o) was thoughtfully designed and synthesized via Cu-catalysed azide-alkyne cycloaddition (CuAAC) click reaction while taking into ...account the varied medicinal activities of indole, oxindole, and 1,2,3-triazole derivatives. By employing the broth micro dilution method, the antimicrobial potential of each synthesized hybrid molecule was examined against three gram-negative (
Escherichia coli, Pseudomonas aeruginosa,
and
Klebsiella pneumonia
), three gram-positive (
Bacillus subtilis, Staphylococcus aureus,
and
Streptococcus pyogenes
), and two fungal strains (
Candida albicans
and
Aspergillus niger
). Compound 5e was shown to be the best antibacterial agent with a minimum inhibitory concentration (MIC) of 25 μg/mL against
Escherichia coli
among all the synthetics. Molecular docking study also streamlined the plausible interactions of compound 5e with the active site of DNA gyrase. The SwissADME webserver analysis revealed that the majority of synthetic compounds adhere to the principles of drug-likeness.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate the short-term effectiveness of overminus spectacles in improving control of childhood intermittent exotropia (IXT).
Randomized, clinical trial.
A total of 58 children aged 3 to <7 years ...with IXT. Eligibility criteria included a distance control score of 2 or worse (mean of 3 measures during a single examination) on a scale of 0 (exophoria) to 5 (constant exotropia) and spherical equivalent refractive error between -6.00 diopters (D) and +1.00 D.
Children were randomly assigned to overminus spectacles (-2.50 D over cycloplegic refraction) or observation (non-overminus spectacles if needed or no spectacles) for 8 weeks.
The primary outcome was distance control score for each child (mean of 3 measures during a single examination) assessed by a masked examiner at 8 weeks. Outcome testing was conducted with children wearing their study spectacles or plano spectacles for the children in the observation group who did not need spectacles. The primary analysis compared mean 8-week distance control score between treatment groups using an analysis of covariance model that adjusted for baseline distance control, baseline near control, prestudy spectacle wear, and prior IXT treatment. Treatment side effects were evaluated using questionnaires completed by parents.
At 8 weeks, mean distance control was better in the 27 children treated with overminus spectacles than in the 31 children who were observed without treatment (2.0 vs. 2.8 points, adjusted difference = -0.75 points favoring the overminus group; 2-sided 95% confidence interval, -1.42 to -0.07 points). Side effects of headaches, eyestrain, avoidance of near activities, and blur appeared similar between treatment groups.
In a pilot randomized clinical trial, overminus spectacles improved distance control at 8 weeks in children aged 3 to <7 years with IXT. A larger and longer randomized trial is warranted to assess the effectiveness of overminus spectacles in treating IXT, particularly the effect on control after overminus treatment has been discontinued.
Kimura disease is a rare chronic inflammatory disorder of unknown etiology. The disease is primarily seen in young Asian males and is characterized by painless subcutaneous swelling. It is often ...accompanied by renal involvement, predominantly manifesting as nephrotic syndrome. We describe a case of Kimura disease in a 69-year-old Indian male, presenting with left postauricular swelling. Clinical and histopathological characteristics are described along with a brief review of the literature
BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The ...disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.
Purpose
The rostrum of a paddlefish provides hydrodynamic stability during feeding process in addition to detect the food using receptors that are randomly distributed in the rostrum. The exterior ...tissue of the rostrum covers the cartilage that surrounds the bones forming interlocking star shaped bones.
Design/methodology/approach
The aim of this work is to assess the mechanical behavior of four finite element models varying the type of formulation as follows: linear-reduced integration, linear-full integration, quadratic-reduced integration and quadratic-full integration. The paper also presents the load transfer mechanisms of the bone structure of the rostrum. The base material used in the study was steel with elastic–plastic behavior as a homogeneous material before applying materials properties that represents the behavior of bones, cartilages and tissues.
Findings
Conclusions are based on comparison among the four models. There is no significant difference between integration orders for similar type of elements. Quadratic-reduced integration formulation resulted in lower structural stiffness compared with linear formulation as seen by higher displacements and stresses than using linearly formulated elements. It is concluded that second-order elements with reduced integration are the alternative to analyze biological structures as they can better adapt to the complex natural contours and can model accurately stress concentrations and distributions without over stiffening their general response.
Originality/value
The use of advanced computational mechanics techniques to analyze the complex geometry and components of the paddlefish rostrum provides a viable avenue to gain fundamental understanding of the proper finite element formulation needed to successfully obtain the system behavior and hot spot locations.
This volume addresses the issue of Hindu peasant women's ability to effectuate the statutory rights to succession and assert ownership of their share in family land. The work combines a critical ...evaluation of law with economic analyses into allocation of resources within the family as a means of addressing gender relations and explaining resulting gender inequalities.
PDF
