Micellar formulations of Crizotinib and Dasatinib in the management of glioblastoma multiforme

Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation.     

Synthesis and biological evaluation of pyrrole-2-carboxamide derivatives: oroidin analogues

The reaction of pyrrole or dibromopyrrole-2-trichloroacetone with various amines results in the series of novel pyrrole-2-carboxamide bearing aromatic heterocycle or aryl or alkyl groups. Synthesized molecules were evaluated for their in vitro antibacterial activities. Most of the compounds exhibited potent activity against both Gram-positive and negative pathogens.     

Investigation of dual-bend serpentine/spiral waveguides coupled to a microchannel system for competent,evanescent-wave-absorption-based,on-chip,biological-/chemical-sensing applications

U or C-shaped waveguides, coupled to analyte microchannels, have been shown to be very responsive to evanescent-wave-absorption-based sensing. However, due to only having a single C-bend length, for analyte interaction in earlier devices, there was always an opportunity to advance their evanescent-absorbance sensitivity, by including multiple C-bend structures (interfaced with the analyte microchannel system) in the device design. To achieve this objective, two different types of waveguide probes (having a different orientation of two C-bends), i.e. S-bend and spiral-bend, were theoretically analyzed and further, experimentally tested for their comparative sensitivity to evanescent wave absorption, in this pioneering study. A novel single-step fabrication procedure (using an SU-8 photoresist), was executed to fabricate these waveguide structures interfaced (both at their inner and outer bend surfaces) with a microchannel system, along with fiber-to-waveguide coupler structures. Experimentally, the sensitivity of the S-bend waveguides was found to be ∼25% higher compared to that of spiral waveguides of similar dimensions, which corroborated the results from numerical modeling. Compared to our earlier embedded C-bend waveguides, the overall evanescent-wave-absorption-based detection sensitivity of the embedded spiral and S-bend waveguides were found to be improved by ∼7.5 times and ∼9 times respectively. Finally, these devices were found to be ideally suited for more sensitive biological-, as well as, chemical-sensing applications, provided a suitable surface alteration process is performed to these waveguide probes. Further, the proposed device has a possible capability for: facile continuous (real-time) analysis, a fixed sample volume interaction, and control over the evaporation of analyte samples introduced in to the device.

The reported device is a versatile sensing-platform, with high sensitivity, for any chemical/biological-sensing applications, if suitable surface adaptation is first performed to the microchannel-system-embedded duel-bend waveguide-probe.     

Public Health Perspectives on Hearing Loss and Aging Outcomes: The Association of Vision,Hearing, and Dual-Sensory Loss with Walking Speed and Incident Slow Walking: Longitudinal and Time to Event Analyses in the Health and Retirement Study

With the aging of the population, vision (VL), hearing (HL), and dual-sensory (DSL, concurrent VL and HL) loss will likely constitute important public health challenges. Walking speed is an indicator of functional status and is associated with mortality. Using the Health and Retirement Study, a nationally representative U.S. cohort, we analyzed the longitudinal relationship between sensory loss and walking speed. In multivariable mixed effects linear models, baseline walking speed was slower by 0.05 m/s (95% confidence interval [CI] = 0.04–0.07) for VL, 0.02 (95% CI = 0.003–0.03) for HL, and 0.07 (95% CI = 0.05–0.08) for DSL compared with those without sensory loss. Similar annual declines in walking speeds occurred in all groups. In time-to-event analyses, the risk of incident slow walking speed (walking speed < 0.6 m/s) was 43% (95% CI = 25–65%), 29% (95% CI = 13–48%), and 35% (95% CI = 13–61%) higher among those with VL, HL, and DSL respectively, relative to those without sensory loss. The risk of incident very slow walking speed (walking speed < 0.4 m/s) was significantly higher among those with HL and DSL relative to those without sensory loss, and significantly higher among those with DSL relative to those with VL or HL alone. Addressing sensory loss and teaching compensatory strategies may help mitigate the effect of sensory loss on walking speed.     

Smoldering multiple myeloma: present position and potential promises

Since smoldering multiple myeloma (SMM) was first described over three decades ago based on a case series of six patients, its definition and our understanding of the entity have evolved considerably. The risk of progression to symptomatic myeloma (MM) varies greatly among individuals diagnosed with myeloma precursor disease. Epidemiologic, molecular, flow cytometric and radiological techniques have demonstrated that this transformation to MM from precursor states is not sudden but rather a continuous overlapping series of events with evidence of end‐organ damage that could manifest in the earliest stages of disease. Contemporary antimyeloma therapies can yield rapid, deep, and durable responses with manageable toxicities, and molecular‐cell‐based measures are now available to rule out minimal residual disease. With this information, clinical studies with correlative measures can now be developed to test the fundamental hypothesis that intervention in early myeloma may provide a measurable clinical benefit to patients by either delaying progression or eradicating plasma cell clones.