Chemokines and chemokine receptors in susceptibility to HIV-1 infection and progression to AIDS

A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.     

Aerosolized recombinant human lysozyme enhances the bactericidal effect of tobramycin in a hamster model of Pseudomonas aeruginosa-induced pneumonia

Previous studies from this laboratory have shown that aerosolized recombinant human lysozyme (rhLZ) mitigates Pseudomonas aeruginosa (PA)-induced pneumonia. In the current investigation, our laboratory tested the hypothesis that aerosolized rhLZ can potentiate the effects of tobramycin (TBMN), thereby reducing the effective dose of this agent in the treatment of PA-induced pneumonia. Syrian hamsters were instilled intratracheally with PA, then exposed to an aerosol containing either 1% rhLZ, 3 μg TBMN, or a combination of both agents. In contrast to the initial studies with rhLZ, which involved 3 separate aerosol exposures, only a single treatment was used in the current investigation. Twenty-four hours after completion of the aerosol regimen, the following parameters were measured: (1) whole-lung colony-forming units (CFU), (2) total bronchoalveolar lavage fluid (BALF) CFU, (3) lung histopathology, and (4) total BALF neutrophils. The combination of rhLZ and TBMN significantly reduced whole-lung and BALF CFU, as well as the inflammatory index, compared to TBMN alone. Similar results were seen in vitro with regard to bactericidal activity. These findings provide a rationale for clinical testing of rhLZ as an adjunct to commercial antibiotic treatment.     

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

Osteoarthritis: Prognosis and emerging therapeutic approach for disease management

Osteoarthritis (OA), a disorder of joints, is prevalent in older age. The contemporary cure for OA is aimed to confer symptomatic relief, consisting of temporary pain and swelling relief. In this paper, we discuss various modalities responsible for the onset of OA and associated with its severity. Inhibition of chondrocytes receptors such as DDR2, SDF‐1, Asporin, and CXCR4 by specific pharmacological inhibitors attenuates OA, a critical step for finding potential disease modifying drugs. We critically analyzed recent OA studies with an emphasis on intermediate target molecules for OA intervention. We also explored some novel and safe treatments for OA by considering disease prognosis crosstalk with cellular signaling pathways.     

What is the Responsiveness and Respondent Burden of the New Knee Society Score?

Background

Although the new Knee Society score (NKSS) has been validated by a task force, a longitudinal study of the same cohort of patients to evaluate the score’s responsiveness and respondent burden has not been reported, to our knowledge.

Questions/Purposes

We analyzed the NKSS for (1) responsiveness; (2) respondent burden; and (3) convergent validity in 148 patients studied longitudinally during more than 1 year.

Methods

During an 8-month period, 165 patients underwent TKA by the same surgeon at our institution, of whom 148 (90%) completed this study; the others were excluded because of distance to travel or loss to followup at the specified time. The NKSS, WOMAC, and SF-12 were completed by each patient 1 day before surgery and at 3 and 12 months postoperatively. At the same times, the original KSS (OKSS) which is designed as an observer’s assessment, was completed by the same orthopaedic fellow for all patients. Responsiveness of the NKSS was assessed by determining effect size, standardized response mean (SRM), and ceiling and floor effects. Respondent burden was assessed through time to completion recorded in minutes and ease of completion which was measured objectively on a Likert scale of 1 to 5 by the patients. Convergent validity was assessed by correlating the NKSS with the WOMAC, SF-12, and OKSS (current, widely used scales) by Pearson’s correlation coefficient.

Results

Effect size was largest (2.83 and 3.38) and SRM was highest (2.29 and 2.68) for the NKSS at 3 and 12 months respectively, indicating the NKSS to be the most-responsive score followed by the OKSS, WOMAC, and SF-12. The NKSS exhibited no ceiling and floor effects. The NKSS took a longer time to complete (5.49 ± 3.56 minutes) compared with the WOMAC (4.64 ± 3.19 minutes) and SF-12 (4.35 ± 3.27 minutes). The mean difference in time taken for the NKSS versus the WOMAC was 0.85 minutes (95% CI, 0.54–1.17 minutes; p < 0.001) and the mean difference for the NKSS versus the SF-12 was 1.14 minutes (95% CI, 0.76–1.15 minutes; p < 0.001). Its ease of completion generally was comparable to that of the WOMAC and SF-12. Convergent validity showed a strong correlation (r > 0.6; p < 0.001) of the NKSS with the WOMAC at all times and moderate to strong correlation (r = 0.4–0.6; p < 0.001) with the SF-12 and OKSS at the first two assessments, which became strong (r > 0.6; p < 0.001) at 12 months.

Conclusions

The NKSS exhibited greater responsiveness than the WOMAC, SF-12, and OKSS scales and showed no ceiling effect, indicating adequate potential for recording future improvement. The NKSS also showed reliable convergent validity when correlated with these other scores. However, it posed a greater respondent burden in terms of time to completion.

Clinical Relevance

As independent nondevelopers of the NKSS, we found it to be a responsive tool for assessment of TKA outcomes. We have confirmed that the NKSS can be used interchangeably for this purpose with the WOMAC scale and that it correlates positively with other established scales of the SF-12 and OKSS. Further study of the short-form version will establish whether it also can be used effectively while reducing the respondent burden.

     

Interference from Proteins and Surfactants on Particle Size Distributions Measured by Nanoparticle Tracking Analysis (NTA)

Purpose

Characterization of submicron protein particles continues to be challenging despite active developments in the field. NTA is a submicron particle enumeration technique, which optically tracks the light scattering signal from suspended particles undergoing Brownian motion. The submicron particle size range NTA can monitor in common protein formulations is not well established. We conducted a comprehensive investigation with several protein formulations along with corresponding placebos using NTA to determine submicron particle size distributions and shed light on potential non-particle origin of size distribution in the range of approximately 50–300 nm.

Methods

NTA and DLS are performed on polystyrene size standards as well as protein and placebo formulations.

Results

Protein formulations filtered through a 20 nm filter, with and without polysorbate-80, show NTA particle counts. As such, particle counts above 20 nm are not expected in these solutions. Several other systems including positive and negative controls were studied using NTA and DLS.

Conclusions

These apparent particles measured by NTA are not observed in DLS measurements and may not correspond to real particles. The intent of this article is to raise awareness about the need to interpret particle counts and size distribution from NTA with caution.