A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update

The blood-brain barrier (BBB) is a diffusion barrier that has an important role in maintaining a precisely regulated microenvironment protecting the neural tissue from infectious agents and toxins in the circulating system. Compromised BBB integrity plays a major role in the pathogenesis of retroviral associated neurological diseases. Human Immunodeficiency Virus (HIV) infection in the Central Nervous System (CNS) is an early event even before the serodiagnosis for HIV positivity or the initiation of antiretroviral therapy (ART), resulting in neurological complications in many of the infected patients. Macrophages, microglia and astrocytes (in low levels) are the most productively/latently infected cell types within the CNS. In this brief review, we have discussed about the effect of HIV infection and viral proteins on the integrity and function of BBB, which may contribute to the progression of HIV associated neurocognitive disorders

Pediatric multiple sclerosis: update on diagnostic criteria, imaging, histopathology and treatment choices

Pediatric multiple sclerosis (MS) represents less than 5% of the MS population, but patients with pediatric-onset disease reach permanent disability at a younger age than adult onset patients. Accurate diagnosis at presentation and optimal long-term treatment is vital to mitigate ongoing neuroinflammation and irreversible neurodegeneration. However, it may be difficult to early differentiate pediatric MS from acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) as they often have atypical presentation that differs from that of adult-onset MS. The purpose of this review is to summarize the updated views on diagnostic criteria, imaging, histopathology and treatment choices

Proteomic Modeling for HIV-1 Infected Microglia-Astrocyte Crosstalk

Background: HIV-1-infected and immune competent brain mononuclear phagocytes (MP; macrophages and microglia) secrete cellular and viral toxins that affect neuronal damage during advanced disease. In contrast, astrocytes can affect disease by modulating the nervous system’s microenvironment. Interestingly, little is known how astrocytes communicate with MP to influence disease. Methods and Findings: MP-astrocyte crosstalk was investigated by a proteomic platform analysis using vesicular stomatitis virus pseudotyped HIV infected murine microglia. The microglial-astrocyte dialogue was significant and affected microglial cytoskeleton by modulation of cell death and migratory pathways. These were mediated, in part, through F-actin polymerization and filament formation. Astrocyte secretions attenuated HIV-1 infected microglia neurotoxicity and viral growth linked to the regulation of reactive oxygen species. Conclusions: These observations provide unique insights into glial crosstalk during disease by supporting astrocytemediated regulation of microglial function and its influence on the onset and progression of neuroAIDS. The results open new insights into previously undisclosed pathogenic mechanisms and open the potential for biomarker discovery an

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB–regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Early galaxy formation and its large-scale effects

Galaxy formation is at the heart of our understanding of cosmic evolution. Although there is a consensus that galaxies emerged from the expanding matter background by gravitational instability of primordial fluctuations, a number of additional physical processes must be understood and implemented in theoretical models before these can be reliably used to interpret observations. In parallel, the astonishing recent progresses made in detecting galaxies that formed only a few hundreds of million years after the Big Bang is pushing the quest for more sophisticated and detailed studies of early structures. In this review, we combine the information gleaned from different theoretical models/studies to build a coherent picture of the Universe in its early stages which includes the physics of galaxy formation along with the impact that early structures had on large-scale processes as cosmic reionization and metal enrichment of the intergalactic medium

Backup reprovisioning with partial protection for disaster-survivable software-defined optical networks

As networks grow in size, large-scale failures caused by disasters may lead to huge data loss, especially in an optical network employing wavelength-division multiplexing (WDM). Providing 100 % protection against disasters would require massive and economically unsustainable bandwidth overprovisioning, as disasters are difficult to predict, statistically rare, and may create large-scale failures. Backup reprovisioning schemes are proposed to remedy this problem, but in case of a large-scale disaster, even the flexibility provided by backup reprovisioning may not be enough, given the sudden reduction in available network resource, i.e., resource crunch. To mitigate the adverse effects of resource crunch, an effective resource reallocation is possible by exploiting service heterogeneity, specifically degraded-service tolerance, which makes it possible to provide some level of service, e.g., reduced capacity, to connections that can tolerate degraded service, versus no service at all. Software-Defined Networking (SDN) is a promising approach to perform such dynamic changes (redistribution of network resources) as it simplifies network management via centralized control logic. By exploiting these new opportunities, we propose a Backup Reprovisioning with Partial Protection (BRPP) scheme supporting dedicated-path protection, where backup resources are reserved but not provisioned (as in shared-path protection), such that the amount of bandwidth reserved for backups as well as their routings are subject to dynamic changes, given the network state, to increase utilization. The performance of the proposed scheme is evaluated by means of SDN emulation using Mininet environment and OpenDaylight as the controller

Disk Diffusion Method for Fluconazole Susceptibility Testing of Candida albicans

This study evaluated the usefulness of the disk diffusion method by using different media for the susceptibility testing of fluconazole against Candida albicans strains. The susceptibility of 108 clinical isolates of C. albicans against fluconazole were determined by microdilution and disk diffusion methods by using RPMI 1640 agar and 25 mug disks. 93 of these isolates were also tested by disk diffusion technique on four different media (yeast nitrogen base agar, Sabouraud dextrose agar, Mueller Hinton agar and Mueller Hinton methylene blue agar). The results of the microdilution method were evaluated visually and optically. The disk diffusion results were determined after 24 and 48 hours of incubation. When the 24-hour zone diameters were compared to the minimal inhibitory concentrations determined visually and optically, the best results were obtained for RPMI 1640 agar and yeast nitrogen base agar. The correlation coefficients were r=-0.34, -0.41 and r=-0.33, -0.32 for the first and second media, respectively. The best values (r=-0.29, -0.39) were obtained for Mueller Hinton methylene blue agar when the 48-hour zone diameters were considered. Agreement between the disk diffusion and microdilution methods was best for RPMI 1640, yeast nitrogen base and Mueller Hinton methylene blue agar after 24 hours of incubation (87-89%, 88-90%, 93-96%, respectively) and for Mueller Hinton methylene blue agar after 48 hours of incubation (89-96%). Disk diffusion method using RPMI 1640, yeast nitrogen base and Mueller Hinton methylene blue agar appears to be a useful, rapid and reliable screening technique for testing the susceptibility of C. albicans strains to fluconazole