17 research outputs found
High content live cell imaging for the discovery of new antimalarial marine natural products
<p>Abstract</p> <p>Background</p> <p>The human malaria parasite remains a burden in developing nations. It is responsible for up to one million deaths a year, a number that could rise due to increasing multi-drug resistance to all antimalarial drugs currently available. Therefore, there is an urgent need for the discovery of new drug therapies. Recently, our laboratory developed a simple one-step fluorescence-based live cell-imaging assay to integrate the complex biology of the human malaria parasite into drug discovery. Here we used our newly developed live cell-imaging platform to discover novel marine natural products and their cellular phenotypic effects against the most lethal malaria parasite, <it>Plasmodium falciparum</it>.</p> <p>Methods</p> <p>A high content live cell imaging platform was used to screen marine extracts effects on malaria. Parasites were grown <it>in vitro </it>in the presence of extracts, stained with RNA sensitive dye, and imaged at timed intervals with the BD Pathway HT automated confocal microscope.</p> <p>Results</p> <p>Image analysis validated our new methodology at a larger scale level and revealed potential antimalarial activity of selected extracts with a minimal cytotoxic effect on host red blood cells. To further validate our assay, we investigated parasite's phenotypes when incubated with the purified bioactive natural product bromophycolide A. We show that bromophycolide A has a strong and specific morphological effect on parasites, similar to the ones observed from the initial extracts.</p> <p>Conclusion</p> <p>Collectively, our results show that high-content live cell-imaging (HCLCI) can be used to screen chemical libraries and identify parasite specific inhibitors with limited host cytotoxic effects. All together we provide new leads for the discovery of novel antimalarials.</p
Potent Fluorinated Agelastatin Analogues for Chronic Lymphocytic Leukemia: Design, Synthesis, and Pharmacokinetic Studies
Chronic
lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in
Western societies and is currently incurable. Multiple treatment options
are practiced, but the available small molecule drugs suffer from
dose-limiting toxicity and undesirable side effects. The need for
new, less toxic treatments is a pressing concern. Here, we demonstrate
that (−)-agelastatin A (<b>1a</b>), a pyrrole-imidazole
alkaloid obtained from a marine sponge, exhibits potent in vitro activity
against primary cell lines of CLL and disclose the synthesis of several
analogues that are equipotent or exceed the potency of the natural
product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl
agelastatin A (<b>1j</b>), showed higher activity than the natural
product when tested against the same cell lines and is the most potent
agelastatin derivative reported to date. A detailed in vitro structure–activity
relationship of <b>1a</b> in CLL compared to that of 22 synthetic
analogues is described along with preliminary in vivo pharmacokinetic
and metabolism studies on the most potent compounds
Incorporating PROMIS Symptom Measures into Primary Care Practice-a Randomized Clinical Trial
BACKGROUND:
Symptoms account for more than 400 million clinic visits annually in the USA. The SPADE symptoms (sleep, pain, anxiety, depression, and low energy/fatigue) are particularly prevalent and undertreated.
OBJECTIVE:
To assess the effectiveness of providing PROMIS (Patient-Reported Outcome Measure Information System) symptom scores to clinicians on symptom outcomes.
DESIGN:
Randomized clinical trial conducted from March 2015 through May 2016 in general internal medicine and family practice clinics in an academic healthcare system.
PARTICIPANTS:
Primary care patients who screened positive for at least one SPADE symptom.
INTERVENTIONS:
After completing the PROMIS symptom measures electronically immediately prior to their visit, the 300 study participants were randomized to a feedback group in which their clinician received a visual display of symptom scores or a control group in which scores were not provided to clinicians.
MAIN MEASURES:
The primary outcome was the 3-month change in composite SPADE score. Secondary outcomes were individual symptom scores, symptom documentation in the clinic note, symptom-specific clinician actions, and patient satisfaction.
KEY RESULTS:
Most patients (84%) had multiple clinically significant (T-score ≥ 55) SPADE symptoms. Both groups demonstrated moderate symptom improvement with a non-significant trend favoring the feedback compared to control group (between-group difference in composite T-score improvement, 1.1; P = 0.17). Symptoms present at baseline resolved at 3-month follow-up only one third of the time, and patients frequently still desired treatment. Except for pain, clinically significant symptoms were documented less than half the time. Neither symptom documentation, symptom-specific clinician actions, nor patient satisfaction differed between treatment arms. Predictors of greater symptom improvement included female sex, black race, fewer medical conditions, and receiving care in a family medicine clinic.
CONCLUSIONS:
Simple feedback of symptom scores to primary care clinicians in the absence of additional systems support or incentives is not superior to usual care in improving symptom outcomes
Halisphingosines A and B, Modified Sphingoid Bases from <i>Haliclona tubifera</i>. Assignment of Configuration by Circular Dichroism and van’t Hoff’s Principle of Optical Superposition
Halisphingosines A (<b>1</b>) and B (<b>2</b>), modified
long-chain sphingoid bases, from the marine sponge <i>Haliclona
tubifera</i> collected in Brazil, were characterized after conversion
to their <i>N</i>-Boc derivatives. The 2<i>R</i>,3<i>R</i>,6<i>R</i> configuration of halisphingosine
A, a compound first reported from <i>Haliclona</i> sp. from
South Korea, was confirmed using a novel CD approach: deconvolution
of exciton coupling from mono- and trinaphthoyl derivatives obtained
by derivatization of the natural product. The sensitive CD deconvolution
method, applicable to submilligram samples, simultaneously predicted
the relative and absolute configuration of three stereocenters in
halisphingosine A with precision and accuracy. Halisphingosine B was
assigned by correlation to halisphingosine A