123 research outputs found
Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia
Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis.
Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors.
Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML
Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F
The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplasmic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate. Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3 as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work may also inspire further exploration of ring-opened analogues of other resin glycosides
Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F
The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α
and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplas mic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a
molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused
by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological
assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin
glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic
inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests
that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most
likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate.
Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3
as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F
and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work
may also inspire further exploration of ring-opened analogues of other resin glycosides
Interplay in galectin expression predicts patient outcomes in a spatially restricted manner in PDAC
BACKGROUND: Galectins (Gal's) are a family of carbohydrate-binding proteins that are known to support the tumour microenvironment through their immunosuppressive activity and ability to promote metastasis. As such they are attractive therapeutic targets, but little is known about the cellular expression pattern of galectins within the tumour and its neighbouring stromal microenvironment. Here we investigated the cellular expression pattern of Gals within pancreatic ductal adenocarcinoma (PDAC).METHODS: Galectin gene and protein expression were analysed by scRNAseq (n=4) and immunofluorescence imaging (n=19) in fibroblasts and epithelial cells of pancreatic biopsies from PDAC patients. Galectin surface expression was also assessed on tumour adjacent normal fibroblasts and cancer associated primary fibroblasts from PDAC biopsies using flow cytometry.RESULTS: scRNAseq revealed higher Gal-1 expression in fibroblasts and higher Gal-3 and -4 expression in epithelial cells. Both podoplanin (PDPN+, stromal/fibroblast) cells and EpCAM+ epithelial cells expressed Gal-1 protein, with highest expression seen in the stromal compartment. By contrast, significantly more Gal-3 and -4 protein was expressed in ductal cells expressing either EpCAM or PDPN, when compared to the stroma. Ductal Gal-4 cellular expression negatively correlated with ductal Gal-1, but not Gal-3 expression. Higher ductal cellular expression of Gal-1 correlated with smaller tumour size and better patient survival. CONCLUSIONS: In summary, the intricate interplay and cell-specific expression patterns of galectins within the PDAC tissue, particularly the inverse correlation between Gal-1 and Gal-4 in ducts and its significant association with patient survival, highlights the complex molecular landscape underlying PDAC and provides valuable insights for future therapeutic interventions.</p
Deep Drilling in the Time Domain with DECam: Survey Characterization
This paper presents a new optical imaging survey of four deep drilling fields
(DDFs), two Galactic and two extragalactic, with the Dark Energy Camera (DECam)
on the 4 meter Blanco telescope at the Cerro Tololo Inter-American Observatory
(CTIO). During the first year of observations in 2021, 4000 images covering
21 square degrees (7 DECam pointings), with 40 epochs (nights) per field
and 5 to 6 images per night per filter in , , , and/or , have
become publicly available (the proprietary period for this program is waived).
We describe the real-time difference-image pipeline and how alerts are
distributed to brokers via the same distribution system as the Zwicky Transient
Facility (ZTF). In this paper, we focus on the two extragalactic deep fields
(COSMOS and ELAIS-S1), characterizing the detected sources and demonstrating
that the survey design is effective for probing the discovery space of faint
and fast variable and transient sources. We describe and make publicly
available 4413 calibrated light curves based on difference-image detection
photometry of transients and variables in the extragalactic fields. We also
present preliminary scientific analysis regarding Solar System small bodies,
stellar flares and variables, Galactic anomaly detection, fast-rising
transients and variables, supernovae, and active galactic nuclei.Comment: 22 pages, 17 figures, 2 tables. Accepted to MNRA
From Data to Software to Science with the Rubin Observatory LSST
The Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) dataset
will dramatically alter our understanding of the Universe, from the origins of
the Solar System to the nature of dark matter and dark energy. Much of this
research will depend on the existence of robust, tested, and scalable
algorithms, software, and services. Identifying and developing such tools ahead
of time has the potential to significantly accelerate the delivery of early
science from LSST. Developing these collaboratively, and making them broadly
available, can enable more inclusive and equitable collaboration on LSST
science.
To facilitate such opportunities, a community workshop entitled "From Data to
Software to Science with the Rubin Observatory LSST" was organized by the LSST
Interdisciplinary Network for Collaboration and Computing (LINCC) and partners,
and held at the Flatiron Institute in New York, March 28-30th 2022. The
workshop included over 50 in-person attendees invited from over 300
applications. It identified seven key software areas of need: (i) scalable
cross-matching and distributed joining of catalogs, (ii) robust photometric
redshift determination, (iii) software for determination of selection
functions, (iv) frameworks for scalable time-series analyses, (v) services for
image access and reprocessing at scale, (vi) object image access (cutouts) and
analysis at scale, and (vii) scalable job execution systems.
This white paper summarizes the discussions of this workshop. It considers
the motivating science use cases, identified cross-cutting algorithms,
software, and services, their high-level technical specifications, and the
principles of inclusive collaborations needed to develop them. We provide it as
a useful roadmap of needs, as well as to spur action and collaboration between
groups and individuals looking to develop reusable software for early LSST
science.Comment: White paper from "From Data to Software to Science with the Rubin
Observatory LSST" worksho
Type 2 Diabetes as a Risk Factor for Dementia in Women Compared With Men:A Pooled Analysis of 2.3 Million People Comprising More Than 100,000 Cases of Dementia
OBJECTIVE: Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia. RESEARCH DESIGN AND METHODS: A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses. RESULTS: Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001). CONCLUSIONS: Individuals with type 2 diabetes are at ~60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women
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