Search

IntroductionAnti-CD40 agonistic antibody (αCD40), an activator of dendritic cells (DC) can enhance antigen presentation and activate cytotoxic T-cells against poorly immunogenic tumors. However, cancer immunotherapy trials also suggest that αCD40 is only moderately effective in patients, falling short of achieving clinical success. Identifying factors that decrease αCD40 immune-stimulating effects can aid the translation of this agent to clinical reality.Method/ResultsHere, we reveal that β-adrenergic signaling on DCs directly interferes with αCD40 efficacy in immunologically cold head and neck tumor model. We discovered that β-2 adrenergic receptor (β2AR) activation rewires CD40 signaling in DCs by directly inhibiting the phosphorylation of IκBα and indirectly by upregulating levels of phosphorylated-cAMP response element-binding protein (pCREB). Importantly, the addition of propranolol, a pan β-Blocker reprograms the CD40 pathways, inducing superior tumor regressions, increased infiltration of cytotoxic T-cells, and a reduced burden of regulatory T-cells in tumors compared to monotherapy.ConclusionOur study highlights an important mechanistic link between stress-induced β2AR signaling and reduced αCD40 efficacy in cold tumors, providing a new combinatorial approach to improve clinical outcomes in patients.

Chronic bone infection caused by Staphylococcus aureus biofilms in children and adults is characterized by reduced antibiotic sensitivity. In this study, we assessed ‘heat-targeted, on-demand’ antibiotic delivery for S. aureus killing by combining ciprofloxacin (CIP)-laden low-temperature sensitive liposomes (LTSLs) with local high-intensity focused ultrasound (HIFU) induced bone heating in a rat model of bone infection. CIP-LTSLs were prepared using the thin-film hydration and extrusion method. Bone infection was established by surgically implanting an orthopedic K-wire colonized with methicillin-resistant S. aureus (MRSA) strain into rat’s femurs. For bone heating, ultrasound-guided HIFU exposures were performed to achieve a local temperature of 40–42 °C (∼15 min) concurrently with intravenous injection of CIP-LTSLs or CIP. CIP biodistribution was determined spectrophotometrically and therapeutic efficacy was determined by bacteriological, histological and scanning electron microscopy (SEM) analyses. CIP-LTSLs in the range of 183.5 nm ± 1.91 showed an encapsulation efficiency of >70% at 37 °C and a complete release at ∼42 °C. The metal implantation method yielded medullary osteomyelitis characterized by suppurative changes (bacterial and pus pockets) by day 10 in bones and adjoining muscle tissues. HIFU heating significantly improved CIP delivery from LTSLs in bones, resulting in a significant reduction in MRSA load compared to HIFU and CIP alone groups. These were also verified by histology and SEM, wherein a distinct reduction in S. aureus population in the infected metal wires and tissues from the combinatorial therapy was noted. HIFU improved CIP delivery to bones, achieving clearance of hard-to-treat MRSA biofilms.

We extend the idea of approximating piecewise smooth univariate functions using rational approximation introduced in \cite{aka_bas-19a} to two-dimensional space. This article aims to implement the novel piecewise Maehly based Pad��-Chebyshev approximation \cite{mae_60a}. We first develop a method referred to as PiPC to approximate univariate piecewise smooth functions and then extend the same to a two-dimensional space, leading to a bivariate piecewise Pad��-Chebyshev approximation (Pi2DPC) for approximating piecewise smooth functions in two-dimension. We study the utility of the proposed techniques in minimizing the Gibbs phenomenon while approximating piecewise smooth functions. The chief advantage of these methods lies in their non-dependence on any apriori knowledge of the locations and types of singularities (if any) present in the original function. Finally, we supplement our methods with numerical results to validate their effectiveness in diminishing the Gibbs phenomenon to negligible levels., 26 pages, 15 figures

Atomic and electronic structures of phosphorene nanoribbons are studied within density functional theory. These novel materials present different physical phenomena expected in two very different physical systems: one dimensional metallic chains and semiconductor surfaces. While `rugged' nanoribbons are semiconducting in their layer-terminnated structures, pure `linear' and `zigzag' nanoribbons are metallic due to metallic edge states. Linear nanoribbons undergo edge reconstruction and zigzag nanoribbons beyond a certain width undergo Peierls transition leading to opening of a band gap in the electronic structure and lowering of total energy. Mixed nanoribbons with linear and zigzag edges on the two sides turn out to be a curious case that display both edge reconstruction and Peierls transition simultaneously. Most phosphoeren nanoribbons turn out to be semiconductors having important implications for their application., Comment: 9 figures including supplementary information