Caregiver Preferences for Three-Dimensional Printed or Augmented Reality Craniosynostosis Skull Models: A Cross-Sectional Survey.

BACKGROUND: Recent advances in three-dimensional (3D) printing and augmented reality (AR) have expanded anatomical modeling possibilities for caregiver craniosynostosis education. The purpose of this study is to characterize caregiver preferences regarding these visual models and determine the impact of these models on caregiver understanding of craniosynostosis. METHODS: The authors constructed 3D-printed and AR craniosynostosis models, which were randomly presented in a cross-sectional survey. Caregivers rated each model's utility in learning about craniosynostosis, learning about skull anatomy, viewing an abnormal head shape, easing anxiety, and increasing trust in the surgeon in comparison to a two-dimensional (2D) diagram. Furthermore, caregivers were asked to identify the fused suture on each model and indicate their preference for generic versus patient-specific models. RESULTS: A total of 412 craniosynostosis caregivers completed the survey (mean age 33 years, 56% Caucasian, 51% male). Caregivers preferred interactive, patient-specific 3D-printed or AR models over 2D diagrams (mean score difference 3D-printed to 2D: 0.16, P < 0.05; mean score difference AR to 2D: 0.17, P < 0.01) for learning about craniosynostosis, with no significant difference in preference between 3D-printed and AR models. Caregiver detection accuracy of the fused suture on the sagittal model was 19% higher with the 3D-printed model than with the AR model (P < 0.05) and 17% higher with the 3D-printed model than with the 2D diagram (P < 0.05). CONCLUSIONS: Our findings indicate that craniosynostosis caregivers prefer 3D-printed or AR models over 2D diagrams in learning about craniosynostosis. Future craniosynostosis skull models with increased user interactivity and patient-specific components can better suit caregiver preferences.

Feasibility of a Planar Coil-Based Inductive-Capacitive Water Level Sensor with a Quality-Detection Feature: An Experimental Study.

This paper presents a new water-level-sensing mechanism based on planar coils fabricated on a printed circuit board (PCB). In addition to level, the sensor detects any relative increase in conductivity compared to that of clean water, which is an indicator of its quality. The sensing mechanism utilizes the eddy current induced in the water column, the corresponding change in the coil inductance, and the change in the turn-to-turn capacitance of the coil in the presence of water. Although several level sensors are available, there is none that gives the level and quality information using a single sensing element. Since both water quantity and quality measurements are fundamental in realizing efficient water and wastewater management, obtaining these two parameters from the same sensor is very beneficial. A scalable, planar coil-based sensor that helps achieve this goal is designed, fabricated, and tested in a laboratory setting. The results illustrate that the reactance of the sensor coil measured at a frequency (1 kHz for the prototype) much lower than the self-resonance of the coil gives reliable information about the level of water, while the measurement made at resonance, using an inductance-to-digital converter, is a clear indicator of its conductivity and, hence, quality.

Image-based scaling laws for somatic growth and pulmonary artery morphometry from infancy to adulthood.

Pulmonary artery (PA) morphometry has been extensively explored in adults, with particular focus on intra-acinar arteries. However, scaling law relationships for length and diameter of extensive preacinar PAs by age have not been previously reported for in vivo human data. To understand preacinar PA growth spanning children to adults, we performed morphometric analyses of all PAs visible in the computed tomography (CT) and magnetic resonance (MR) images from a healthy subject cohort [n = 16; age: 1-51 yr; body surface area (BSA): 0.49-2.01 m2]. Subject-specific anatomic PA models were constructed from CT and MR images, and morphometric information-diameter, length, tortuosity, bifurcation angle, and connectivity-was extracted and sorted into diameter-defined Strahler orders. Validation of Murray's law, describing optimal scaling exponents of radii for branching vessels, was performed to determine how closely PAs conform to this classical relationship. Using regression analyses of vessel diameters and lengths against orders and patient metrics (BSA, age, height), we found that diameters increased exponentially with order and allometrically with patient metrics. Length increased allometrically with patient metrics, albeit weakly. The average tortuosity index of all vessels was 0.026 ± 0.024, average bifurcation angle was 28.2 ± 15.1°, and average Murray's law exponent was 2.92 ± 1.07. We report a set of scaling laws for vessel diameter and length, along with other morphometric information. These provide an initial understanding of healthy structural preacinar PA development with age, which can be used for computational modeling studies and comparison with diseased PA anatomy.NEW & NOTEWORTHY Pulmonary artery (PA) morphometry studies to date have focused primarily on large arteries and intra-acinar arteries in either adults or children, neglecting preacinar arteries in both populations. Our study is the first to quantify in vivo preacinar PA morphometry changes spanning infants to adults. For preacinar arteries > 1 mm in diameter, we identify scaling laws for vessel diameters and lengths with patient metrics of growth and establish a healthy PA morphometry baseline for most preacinar PAs.

Anionic surfactant based reverse micellar extraction of L-asparaginase synthesized by Azotobacter vinelandii.

L-Asparaginase synthesized by Azotobacter vinelandii via submerged fermentation in the presence of sucrose was successfully extracted using Reverse micellar extraction. Single step enzyme purification process was developed by varying the process variables which resulted in maximum specificity and extraction of L-asparaginase. The effect of different variables, including broth pH, addition of alcohol during the forward extraction and pH of the fresh stripping aqueous phase, addition of alcohol and electrolyte during backward extraction process were studied. Lower concentration of butanol resulted in maximum activity of the enzyme during forward extraction while enzyme activity was found to increase further with the addition of higher concentrations of ammonium sulphate during backward extraction. Chromatographic analysis of L-asparaginase peak at ~7.65 min was intense for the back extracted sample confirming the maximum purity of L-asparaginase obtained. Purity of L-asparaginase was increased to about 379.68 fold.

Inhaled drug delivery for the targeted treatment of asthma.

Asthma is a chronic lung disease affecting millions worldwide. While classically acknowledged to result from allergen-driven type 2 inflammatory responses leading to IgE and cytokine production and the influx of immune cells such as mast cells and eosinophils, the wide range in asthmatic pathobiological subtypes lead to highly variable responses to anti-inflammatory therapies. Thus, there is a need to develop patient-specific therapies capable of addressing the full spectrum of asthmatic lung disease. Moreover, delivery of targeted treatments for asthma directly to the lung may help to maximize therapeutic benefit, but challenges remain in design of effective formulations for the inhaled route. In this review, we discuss the current understanding of asthmatic disease progression as well as genetic and epigenetic disease modifiers associated with asthma severity and exacerbation of disease. We also overview the limitations of clinically available treatments for asthma and discuss pre-clinical models of asthma used to evaluate new therapies. Based on the shortcomings of existing treatments, we highlight recent advances and new approaches to treat asthma via inhalation for monoclonal antibody delivery, mucolytic therapy to target airway mucus hypersecretion and gene therapies to address underlying drivers of disease. Finally, we conclude with discussion on the prospects for an inhaled vaccine to prevent asthma.

Nanotheranostic Strategies for Cancer Immunotherapy.

Despite advancements in cancer immunotherapy, heterogeneity in tumor response impose barriers to successful treatments and accurate prognosis. Effective therapy and early outcome detection are critical as toxicity profiles following immunotherapies can severely affect patients' quality of life. Existing imaging techniques, including positron emission tomography, computed tomography, magnetic resonance imaging, or multiplexed imaging, are often used in clinics yet suffer from limitations in the early assessment of immune response. Conventional strategies to validate immune response mainly rely on the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified iRECIST for immuno-oncology drug trials. However, accurate monitoring of immunotherapy efficacy is challenging since the response does not always follow conventional RECIST criteria due to delayed and variable kinetics in immunotherapy responses. Engineered nanomaterials for immunotherapy applications have significantly contributed to overcoming these challenges by improving drug delivery and dynamic imaging techniques. This review summarizes challenges in recent immune-modulation approaches and traditional imaging tools, followed by emerging developments in three-in-one nanoimmunotheranostic systems co-opting nanotechnology, immunotherapy, and imaging. In addition, a comprehensive overview of imaging modalities in recent cancer immunotherapy research and a brief outlook on how nanotheranostic platforms can potentially advance to clinical translations for the field of immuno-oncology is presented.

Targeting macrophages: a novel avenue for cancer drug discovery.

Introduction: Tumor-associated macrophages (TAMs) make up a significant portion of the tumor microenvironment. Emerging clinical evidence indicate that cytokines present in the tumor microenvironment influence TAMs to play an immunosuppressive role by acquiring a pro-tumoral phenotype. However, TAMs are inherently plastic cells that can be phenotypically reprogrammed to elicit an anti-tumoral response. Therapeutic strategies that focus on targeting TAMs have opened new avenues for drug discoveries.Areas covered: This review discusses recent developments in TAM targeted immunotherapy in both preclinical and clinical settings. This article highlights the potential signaling pathways that can be targeted for macrophage reprogramming and discusses the progress of current clinical trials involved in TAMs targeting. Novel nanoparticle-based drug delivery strategies involved in macrophage-based cancer therapeutics and diagnostics are also discussed.Expert opinion: TAM targeted therapies have limited success in clinics due to reasons such as insufficient inhibition of signaling pathways, lower drug accumulation in the tumor, activation of feedback signaling pathways that induce resistance to monotherapies and systemic dose-related toxicities. Nanoparticle-based delivery platforms could overcome these challenges since they enable encapsulation of multiple drugs that target different signaling pathways and enhance intratumoral delivery and can enable delivery of imaging agents.

A Nitric Oxide (NO) Nanoreporter for Noninvasive Real-Time Imaging of Macrophage Immunotherapy.

Macrophage-centered therapeutic approaches that rely on immune modulation of tumor associated macrophages (TAMs) from a pro-tumorigenic phenotype (M2) to an anti-tumorigenic phenotype (M1) have facilitated a paradigm shift in macrophage immunotherapy. However, limited clinical success has been achieved due to the low response rates observed in different types of cancers. The ability to measure immune response in real time is critical in order to differentiate responders from non-responders; however, there are currently no platforms to monitor real-time macrophage immunotherapy response. Hence, there is an immediate need to develop imaging techniques that can longitudinally monitor macrophage immunotherapy response. Nitric oxide (NO) produced as a result of activation of macrophages to an anti-tumorigenic state is considered as a hallmark of M1 and can be a direct indication of response. In this study, a NO nanoreporter (NO-NR) is reported that enables real-time monitoring of macrophage immunotherapy drugs in vitro and in vivo. Furthermore, it is observed that sustained inhibition of colony stimulating factor 1 receptor (CSF1R) using a CSF1R inhibitor-NO-NR system leads to enhanced efficacy and better imaging signal. In conclusion, a first-of-its-kind NO nanoreporter tool is reported that can be used as an activatable imaging agent to monitor macrophage immunotherapy response in real time.

Dual inhibition of CSF1R and MAPK pathways using supramolecular nanoparticles enhances macrophage immunotherapy.

Among the numerous immune interactions, or lack-thereof, that occur during cancer progression, tumor-associated macrophages (TAMs) - cancer cell interactions have been shown to play an important role in modulating the tumor-microenvironment to an immune suppressive mode, promoting accelerated tumor growth, survival and metastatic spread. TAMs are predominantly polarized to a pro-tumorigenic M2-phenotype through macrophage colony stimulating factor 1 (MCSF) cytokines that bind to the colony-stimulating factor 1 receptor (CSF1R), a class III receptor tyrosine kinase. This MCSF-CSF1R interaction results in autophosphorylation of CSF1R and subsequent phosphorylation and activation of downstream signaling pathways including mitogen-activated protein kinase (MAPK) pathway leading to proliferation, survival and functional activity of M2 TAMs. Therapeutic inhibition of CSF1R and MAPK signaling could effectively re-polarize M2 macrophages to an anti-tumorigenic M1 phenotype; however, this is challenging. In this study, we demonstrate that concurrent and sustained inhibition of the CSF1R and MAPK signaling pathways using dual-kinase inhibitor-loaded supramolecular nanoparticles (DSNs) enhance repolarization of pro-tumorigenic M2 macrophages to the anti-tumorigenic M1 phenotype. The supramolecular nanoparticles exhibited physical stability of over 7 days during storage conditions at 4 °C and over 24 h in human serum, released the inhibitors in a sustained manner and showed significantly higher internalization and accumulation of inhibitors in the M2 macrophages even at longer time points. When tested in a highly aggressive 4T1 breast cancer model, the supramolecular nanoparticles accumulated in TAMs at a significantly higher concentration, increased M1-like phenotype at significantly higher proportion and improved anti-tumor efficacy as compared to combination of single-inhibitor nanoparticles or the small molecule inhibitors. Our data suggests that concurrent, vertical inhibition of multiple intracellular kinase signaling pathways is important for repolarization of M2 macrophages to M1 phenotype, and by utilizing dual-inhibitor loaded supramolecular nanoparticles, further increase the ability to produce more M1 macrophages as compared to M2 macrophages in the tumor microenvironment. This results in enhanced tumor growth inhibition and reduced toxicity. Therefore, vertical, co-inhibition of CSF1R and downstream signaling pathways like MAPK could be a promising macrophage immunotherapy strategy for aggressive cancers.

Lipid-based phagocytosis nanoenhancer for macrophage immunotherapy.

Tumor associated macrophages (TAMs) play an important role in initiating the immunosuppressive environment that negatively impacts the immunotherapy efficacy and has long been linked with cancer progression. On the other hand, activated macrophages display immense phagocytic potential and can be used as an effector cell for cancer therapy. But, activating TAMs to effectively phagocytose cancer cells is challenging. Cancer cells upregulate CD47, a "don't eat me" receptor that ligates with SIRPα present on macrophages to downregulate the phagocytosis. Since phagocytosis is a physical phenomenon based on engulfment of aberrant cells, we hypothesized that the phagocytic function of macrophages can be enhanced by blocking both CD47 and SIRPα in tandem and at the same time, engaging both macrophages and cancer cells can favor increased macrophage-cancer cellular interactions. Here, we demonstrate that a simple approach of anti-CD47 and anti-SIRPα antibodies conjugated lipid-based phagocytosis nanoenhancer (LPN) can perform both of these functions. The LPNs were stable in both physiological and biologically relevant conditions, bound to both macrophages and cancer cells and significantly enhanced phagocytosis of cancer cells as compared to combination of free antibodies. LPN treatment showed significant tumor growth inhibition and increased survival in B16F10 melanoma tumor bearing mice with no systemic toxicity. Mechanistic analysis of efficacy revealed an increase in intra-tumoral infiltration of effector T cells and NK cells. Cytokine analysis revealed increased secretion of intracellular iNOS, a hallmark of activated macrophages. This study shows that LPN can simultaneously block both CD47 and SIRPα and can effectively engage macrophage and cancer cell in close proximity. Combining these facets provide a simple approach to enhance phagocytosis and improve anti-cancer macrophage immunotherapy.

Granzyme B nanoreporter for early monitoring of tumor response to immunotherapy.

Despite recent advancements in cancer immunotherapy, accurate monitoring of its efficacy is challenging due to heterogeneous immune responses. Conventional imaging techniques lack the sensitivity and specificity for early response assessment. In this study, we designed a granzyme B (GrB) nanoreporter (GNR) that can deliver an immune checkpoint inhibitor to the tumor and track time-sensitive GrB activity as a direct way to monitor initiation of effective immune responses. Anti-programmed death-ligand 1 (PD-L1) antibody-conjugated GNRs inhibited PD-1/PD-L1 interactions efficiently and induced T cell-mediated GrB release that can be imaged using activatable imaging probe. GNRs enabled real-time immunotherapy response monitoring in a tumor-bearing mice model and distinguished between highly responsive and poorly responsive tumors. Furthermore, increasing doses resulted in a better response and enhanced sensitivity in poorly responsive tumors. These findings indicate that GNR has the potential to serve as a tool for sensitive and noninvasive evaluation of immunotherapy efficacy.

CSF1R- and SHP2-Inhibitor-Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor-Associated Macrophages.

Immune modulation of macrophages has emerged as an attractive approach for anti-cancer therapy. However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1-R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor-associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein α (SIRPα) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain -phosphatases SHP-1 and SHP-2 in macrophages. This results in activation of "eat-me-not" signaling pathway and inhibition of phagocytosis. Here, it is reported that self-assembled dual-inhibitor-loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti-tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1-R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage-based immunotherapy.

Association of pregnant women periodontal status to preterm and low-birth weight babies: A systematic and evidence-based review.

The mouth serves as a mirror to general health and also as a portal for disease to the rest of the body. Since the old wives' tale of "the loss of a tooth for every pregnancy", oral health during pregnancy has long been a focus of interest. In the past decade, there has been mounting scientific evidence suggesting that periodontal disease may play an important role as a risk factor for adverse pregnancy outcomes. Considering all the above stated factors this systematic review is aimed to focus on the association of periodontal diseases to preterm and low-birth weight (LBW) babies. In view of the large body of literature the review is limited to studies identified by computer searching. Hand searching of journals and gathering of unpublished reports and conference proceedings was outside the scope of the review. The PubMed database was searched using the search terms: periodontitis, preterm, LBW. The titles, authors, and abstracts from all studies identified by the electronic search were printed and reviewed independently on the basis of keywords, title and abstract, to determine whether these met the inclusion criteria. The electronic search identified 68 papers. After review of the study title, keywords and abstracts, 62 papers were identified potentially meeting inclusion criteria. Generally, all the studies reviewed in the paper suggest that periodontal disease may be a potential risk factor for preterm LBW babies.