Intelligent Nanocomposites with Intrinsic Blood-Brain-Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma.

The blood-brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo-transferrin (holo-Tf) with in situ growth of MnO2 nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo-Tf to obtain MnO2 @Tf-ppIX nanoparticles (TMP). Because of the functional inheritance of holo-Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.

Automated grading of acne vulgaris by deep learning with convolutional neural networks.

BACKGROUND: The visual assessment and severity grading of acne vulgaris by physicians can be subjective, resulting in inter- and intra-observer variability. OBJECTIVE: To develop and validate an algorithm for the automated calculation of the Investigator's Global Assessment (IGA) scale, to standardize acne severity and outcome measurements. MATERIALS AND METHODS: A total of 472 photographs (retrieved 01/01/2004-04/08/2017) in the frontal view from 416 acne patients were used for training and testing. Photographs were labeled according to the IGA scale in three groups of IGA clear/almost clear (0-1), IGA mild (2), and IGA moderate to severe (3-4). The classification model used a convolutional neural network, and models were separately trained on three image sizes. The photographs were then subjected to analysis by the algorithm, and the generated automated IGA scores were compared to clinical scoring. The prediction accuracy of each IGA grade label and the agreement (Pearson correlation) of the two scores were computed. RESULTS: The best classification accuracy was 67%. Pearson correlation between machine-predicted score and human labels (clinical scoring and researcher scoring) for each model and various image input sizes was 0.77. Correlation of predictions with clinical scores was highest when using Inception v4 on the largest image size of 1200 × 1600. Two sets of human labels showed a high correlation of 0.77, verifying the repeatability of the ground truth labels. Confusion matrices show that the models performed sub-optimally on the IGA 2 label. CONCLUSION: Deep learning techniques harnessing high-resolution images and large datasets will continue to improve, demonstrating growing potential for automated clinical image analysis and grading.

Assessment of Barrett's esophagus and dysplasia with ultrahigh-speed volumetric en face and cross-sectional optical coherence tomography.

BACKGROUND: This study aimed to evaluate the use of ultrahigh-speed volumetric en face and cross-sectional optical coherence tomography (OCT) with micromotor catheters for the in vivo assessment of Barrett's esophagus and dysplasia. METHODS: 74 OCT datasets with correlated biopsy/endoscopic mucosal resection histology (49 nondysplastic Barrett's esophagus [NDBE], 25 neoplasia) were obtained from 14 patients with Barrett's esophagus and a history of dysplasia and 30 with NDBE. The associations between irregular mucosal patterns on en face OCT, absence of mucosal layering, surface signal > subsurface, and > 5 atypical glands on cross-sectional OCT vs. histology and treatment history were assessed by three blinded readers. RESULTS: Atypical glands under irregular mucosal patterns occurred in 75 % of neoplasia (96 % of treatment-naïve neoplasia) vs. 30 % of NDBE datasets (43 % of short- and 18 % of long-segment NDBE). Mucosal layering was absent in 35 % of neoplasia and 50 % of NDBE datasets, and surface signal > subsurface occurred in 29 % of neoplasia and 30 % of NDBE datasets. CONCLUSIONS: Atypical glands under irregular mucosal patterns are strongly associated with neoplasia, suggesting potential markers for dysplasia and a role in pathogenesis.

Endoscopic forward-viewing optical coherence tomography and angiography with MHz swept source.

Endoscopic optical coherence tomography (OCT) instruments are mostly side viewing and rely on at least one proximal scan, thus limiting accuracy of volumetric imaging and en face visualization. Previous forward-viewing OCT devices had limited axial scan speeds. We report a forward-viewing fiber scanning 3D-OCT probe with 900 µm field of view and 5 µm transverse resolution, imaging at 1 MHz axial scan rate in the human gastrointestinal tract. The probe is 3.3 mm diameter and 20 mm rigid length, thus enabling passage through the endoscopic channel. The scanner has 1.8 kHz resonant frequency, and each volumetric acquisition takes 0.17 s with 2 volumes/s display. 3D-OCT and angiography imaging of the colon was performed during surveillance colonoscopy.

Endoscopic optical coherence tomography angiography microvascular features associated with dysplasia in Barrett's esophagus (with video).

BACKGROUND AND AIMS: Angiogenesis is associated with neoplastic progression of Barrett's esophagus (BE). Volumetric optical coherence tomography angiography (OCTA) visualizes subsurface microvasculature without exogenous contrast agents. We investigated the association of OCTA microvascular features with low-grade dysplasia (LGD) and high-grade dysplasia (HGD). METHODS: Fifty-two patients undergoing BE surveillance or endoscopic eradication therapies for dysplasia were imaged using volumetric OCTA and corresponding histologic diagnoses wre obtained to yield 97 data sets (nondysplastic BE [NDBE], 74; LGD, 10; HGD, 13). After evaluating OCTA image quality, 54 datasets (NDBE, 35; LGD, 8; HGD, 11) from 32 patients were used to develop a training and reading protocol. The association of abnormal vessel branching and heterogeneous vessel size with LGD/HGD and a regular honeycomb vessel pattern with NDBE were investigated. RESULTS: Blinded OCTA reading of 41 OCTA datasets (NDBE, 27; LGD, 7; HGD, 7) was performed by readers with various levels of OCT/OCTA experience including 3 OCT trainees, 1 gastroenterologist, and 2 gastroenterology fellows. Among the 6 readers, OCTA features of abnormal vessel branching and heterogeneous vessel size had an overall 94% sensitivity (95% CI, 89-99) and 69% specificity (95% CI, 62-76) for differentiating LGD/HGD versus NDBE with a mean reading time of 45 seconds per data set and moderate (kappa = .58) interobserver agreement. CONCLUSIONS: Volumetric en face OCTA imaging enables rapid examination of depth resolved microvascular features with near-microscopic resolution. OCTA can visualize microvascular features associated with LGD/HGD with high accuracy, which motivates new technologic advances and future studies investigating the diagnostic performance of OCTA.

Correction of rotational distortion for catheter-based en face OCT and OCT angiography.

We demonstrate a computationally efficient method for correcting the nonuniform rotational distortion (NURD) in catheter-based imaging systems to improve endoscopic en face optical coherence tomography (OCT) and OCT angiography. The method performs nonrigid registration using fiducial markers on the catheter to correct rotational speed variations. Algorithm performance is investigated with an ultrahigh-speed endoscopic OCT system and micromotor catheter. Scan nonuniformity is quantitatively characterized, and artifacts from rotational speed variations are significantly reduced. Furthermore, we present endoscopic en face OCT and OCT angiography images of human gastrointestinal tract in vivo to demonstrate the image quality improvement using the correction algorithm.

Compact piezoelectric transducer fiber scanning probe for optical coherence tomography.

We developed a compact, optical fiber scanning piezoelectric transducer (PZT) probe for endoscopic and minimally invasive optical coherence tomography (OCT). Compared with previous forward-mount fiber designs, we present a reverse-mount design that achieves a shorter rigid length. The fiber was mounted at the proximal end of a quadruple PZT tube and scanned inside the hollow PZT tube to reduce the probe length. The fiber resonant frequency was 338 Hz using a 17-mm-long fiber. A 0.9 mm fiber deflection was achieved with a driving amplitude of 35 V. Using a GRIN lens-based optical design with a 1.3× magnification, a ∼6 µm spot was scanned over a 1.2 mm diameter field. The probe was encased in a metal hypodermic tube with a ∼25 mm rigid length and covered with a 3.2 mm outer diameter (OD) plastic sheath. Imaging was performed with a swept source OCT system based on a Fourier domain modelocked laser (FDML) light source at a 240 kHz axial scan rate and 8 µm axial resolution (in air). En face OCT imaging of skin in vivo and human colon ex vivo was demonstrated.

Controlling the proliferation and differentiation stages to initiate periodontal regeneration.

The success of periodontal regeneration depends on the coordination of early cell proliferation and late cell differentiation. The aim of this study was to investigate whether the proliferation or differentiation stage predominantly promotes the initiation of periodontal regeneration. Critical-sized periodontal defects were surgically created on rat maxillae and filled with poly-(D,L-lactide-co-glycolide)-poly-d,l-lactide hybrid microspheres encapsulating platelet-derived growth factor (PDGF, a promoter of mitogenesis), simvastatin (a promoter of osteogenic differentiation), or bovine serum albumin (a control). The encapsulation efficiency and in vitro release profiles of the microspheres were determined by high-performance liquid chromatography and enzyme-linked immunosorbent assay. The maxillae were harvested after 10 or 14 days and assessed by micro-computed tomography, histology, and immunohistochemistry for regeneration efficacy and cell viability. The rapid release of PDGF was observed within the first week, whereas a slow release profile was noted for simvastatin. The PDGF-treated specimens demonstrated a significantly higher bone volume fraction compared with bovine serum albumin- (p < 0.05) or simvastatin-treated (p < 0.05) specimens at day 14. Histologically, active bone formation originating from the defect borders was noted in both the PDGF- and the simvastatin-treated specimens, and functionally aligned periodontal ligament fiber insertion was only observed in the PDGF-treated specimens. The significant promotion of mitogenesis by PDGF treatment was also noted at day 14 (p < 0.05). In conclusion, increased mitogenesis or osteogenic differentiation may stimulate osteogenesis, and the upregulation of mitogenesis by PDGF appears to play a role in the initiation of periodontal regeneration.

Reshaping the Tumor Immune Microenvironment Based on a Light-Activated Nanoplatform for Efficient Cancer Therapy.

The immunosuppressive tumor microenvironment (TME) always causes poor antitumor immune efficacy, prone to relapse and metastasis. Herein, novel poly(vinylpyrrolidone) (PVP) modified BiFeO3 /Bi2 WO6 (BFO/BWO) with a p-n type heterojunction is constructed for reshaping the immunosuppressive TME. Reactive oxygen species can be generated under light activation by the well-separated hole (h+ )-electron (e- ) pairs owing to the heterojunction in BFO/BWO-PVP NPs. Interestingly, h+ can trigger the decomposition of H2 O2 to generate O2 for alleviating tumor hypoxia, which not only sensitizes photodynamic therapy (PDT) and radiotherapy (RT), but also promotes tumor-associated macrophages (TAMs) polarization from M2 to M1 phenotype, which is beneficial to decrease the expression of HIF-1α. Importantly, such a light-activated nanoplatform, combining with RT can efficiently activate and recruit cytotoxic T lymphocytes to infiltrate in tumor tissues, as well as stimulate TAMs to M1 phenotype, dramatically reverse the immunosuppressive TME into an immunoactive one, and further boost immune memory responses. Moreover, BFO/BWO-PVP NPs also present high performance for computed tomography imaging contrast. Taken together, this work offers a novel paradigm for achieving O2 self-supply of inorganic nanoagents and reshaping of the tumor immune microenvironment for effective inhibition of cancer as well as metastasis and recurrence.

Copper-Catalyzed, N-Directed Distal C(sp3)-H Functionalization toward Azepanes.

We herein report a copper-catalyzed formal [5 + 2] aza-annulation of N-fluorosulfonamides and 1,3-dienes/1,3-enynes for synthesis of structurally diverse alkene/alkyne-containing azepanes. The reaction features selective functionalization of distal unactivated C(sp3)-H bonds and a broad substrate scope, thus allowing the late-stage modification of pharmaceuticals and natural products. A radical mechanism involving 1,5-hydrogen atom transfer of N-radicals, facile coupling of alkyl radicals with 1,3-dienes/1,3-enynes, and the construction of azepane motifs via C-N bond formation is proposed.

Effects of Different Pedaling Positions on Muscle Usage and Energy Expenditure in Amateur Cyclists.

BACKGROUND: Inappropriate cycling positions may affect muscle usage strategy and raise the level of fatigue or risk of sport injury. Dynamic bike fitting is a growing trend meant to help cyclists select proper bikes and adjust them to fit their ergometry. The purpose of this study is to investigate how the "knee forward of foot" (KFOF) distance, an important dynamic bike fitting variable, influences the muscle activation, muscle usage strategy, and rate of energy expenditure during cycling. METHODS: Six amateur cyclists were recruited to perform the short-distance ride test (SRT) and the graded exercise tests (GXT) with pedaling positions at four different KFOF distances (+20, 0, -20, and -40 mm). The surface electromyographic (EMG) and portable energy metabolism systems were used to monitor the muscle activation and energy expenditure. The outcome measures included the EMG root-mean-square (RMS) amplitudes of eight muscles in the lower extremity during the SRT, the regression line of the changes in the EMG RMS amplitude and median frequency (MF), and the heart rate and oxygen consumption during the GXT. RESULTS: Our results revealed significant differences in the muscle activation of vastus lateralis, vastus medialis, and semitendinosus among four different pedaling positions during the SRT. During GXT, no statistically significant differences in muscle usage strategy and energy expenditure were found among different KFOF. However, most cyclists had the highest rate of energy expenditure with either KFOF at -40 mm or 20 mm. CONCLUSIONS: The KFOF distance altered muscle activation in the SRT; however, no significant influence on the muscle usage strategy was found in the GXT. A higher rate of energy expenditure in the extreme pedaling positions of KFOF was observed in most amateur cyclists, so professional assistance for proper bike fitting was recommended.

Correction of circumferential and longitudinal motion distortion in high-speed catheter/endoscope-based optical coherence tomography.

Catheter/endoscope-based optical coherence tomography (OCT) is a powerful modality that visualizes structural information in luminal organs. Increases in OCT speed have reduced motion artifacts by enabling acquisition faster than or comparable to the time scales of physiological motion. However motion distortion remains a challenge because catheter/endoscope OCT imaging involves both circumferential and longitudinal scanning of tissue. This paper presents a novel image processing method to estimate and correct motion distortion in both the circumferential and longitudinal directions using a single en face image from a volumetric data set. The circumferential motion distortion is estimated and corrected using the en face image. Then longitudinal motion distortion is estimated and corrected using diversity of image features along the catheter pullback direction. Finally, the OCT volume is resampled and motion corrected. Results are presented on synthetic images and clinical OCT images of the human esophagus.

Design, synthesis, and biological evaluation of hederagenin derivatives with improved aqueous solubility and tumor resistance reversal activity.

Multidrug resistance (MDR) has become a major obstacle to malignancies treatment by chemotherapeutic drugs, therefore, it is important to develop MDR reversal agents with high activity. We have previously found that the hederagenin (HD) derivative HBQ showed good tumor MDR reversal activity in vitro and in vivo but had poor solubility. In this study, to enhance the aqueous solubility and tumor MDR reversal activity of HBQ, three series of HD derivatives were designed and synthesized. Nitrogen-containing heterocyclic-substituted, PEGylated, and ring-A substituted derivatives significantly reversed the MDR phenotype of KBV (multidrug-resistant oral epidermoid carcinoma) cells toward paclitaxel at a concentration of 10 µM in MTT assays. The PEGylated derivatives 10c-10e had increased aqueous solubility compared with HBQ by 18-657 fold, while maintaining tumor MDR reversal activity. The most in vitro active compound 10c possessed good chemical stability to an esterase over 24 h and enhanced the sensitivity of KBV cells to paclitaxel and vincristine with IC50 values of 4.58 and 0.79 nM, respectively. Mechanism studies indicated that compound 10c increased the accumulation of P-glycoprotein (P-gp) substrates rhodamine 123 and Flutax1 in KBV cells and MCF-7T (paclitaxel-resistant breast carcinoma) cells, that is to say, compound 10c exerted the reversal effect of tumor MDR by inhibiting the efflux function of P-gp. Finally, the structure-activity relationships were further investigated by analyzing the relationship between structure and tumor MDR reversal activity of HD derivatives. This study highlights the potential of PEGylated HD derivatives such as compound 10c for the development of tumor MDR reversal agents and provides information for the further improvement of the aqueous solubility and tumor MDR reversal activity of HD derivatives in the future.

Multi-MHz MEMS-VCSEL swept-source optical coherence tomography for endoscopic structural and angiographic imaging with miniaturized brushless motor probes.

Swept source optical coherence tomography (SS-OCT) enables volumetric imaging of subsurface structure. However, applications requiring wide fields of view (FOV), rapid imaging, and higher resolutions have been challenging because multi-MHz axial scan (A-scan) rates are needed. We describe a microelectromechanical systems vertical cavity surface-emitting laser (MEMS-VCSEL) SS-OCT technology for A-scan rates of 2.4 and 3.0 MHz. Sweep to sweep calibration and resampling are performed using dual channel acquisition of the OCT signal and a Mach Zehnder interferometer signal, overcoming inherent optical clock limitations and enabling higher performance. We demonstrate ultrahigh speed structural SS-OCT and OCT angiography (OCTA) imaging of the swine gastrointestinal tract using a suite of miniaturized brushless motor probes, including a 3.2 mm diameter micromotor OCT catheter, a 12 mm diameter tethered OCT capsule, and a 12 mm diameter widefield OCTA probe. MEMS-VCSELs promise to enable ultrahigh speed SS-OCT with a scalable, low cost, and manufacturable technology, suitable for a diverse range of imaging applications.

Protein-based nanoplatforms for tumor imaging and therapy.

Cancer is one of the leading causes of death all over the world. The development of nanoplatform provides a promising strategy for the diagnosis and treatment of cancer. As the foundation of the nanoplatform, the composition of nanocarrier decides the basic properties. Protein exists in all kinds of life and participates in any life activities, having great potentials to serve as a nanocarrier because of its excellent biocompatibility, abundance of functional groups, and inherent biological activity. As a result, protein-based nanoplatforms have evoked extensive interests for tumor imaging and therapy. This review presents the latest progresses on the advancement of protein-based nanoplatforms, introducing the most common protein nanocarriers (such as human/bovine serum albumin, ferritin, human transferrin) thoroughly including their physiochemical properties and specific applications. Also, other kinds of protein are briefly involved. Finally, the prospects and challenges of the development of protein-based nanoplatforms are summarized. This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Resolution enhancement and realistic speckle recovery with generative adversarial modeling of micro-optical coherence tomography.

A resolution enhancement technique for optical coherence tomography (OCT), based on Generative Adversarial Networks (GANs), was developed and investigated. GANs have been previously used for resolution enhancement of photography and optical microscopy images. We have adapted and improved this technique for OCT image generation. Conditional GANs (cGANs) were trained on a novel set of ultrahigh resolution spectral domain OCT volumes, termed micro-OCT, as the high-resolution ground truth (∼1 µm isotropic resolution). The ground truth was paired with a low-resolution image obtained by synthetically degrading resolution 4x in one of (1-D) or both axial and lateral axes (2-D). Cross-sectional image (B-scan) volumes obtained from in vivo imaging of human labial (lip) tissue and mouse skin were used in separate feasibility experiments. Accuracy of resolution enhancement compared to ground truth was quantified with human perceptual accuracy tests performed by an OCT expert. The GAN loss in the optimization objective, noise injection in both the generator and discriminator models, and multi-scale discrimination were found to be important for achieving realistic speckle appearance in the generated OCT images. The utility of high-resolution speckle recovery was illustrated by an example of micro-OCT imaging of blood vessels in lip tissue. Qualitative examples applying the models to image data from outside of the training data distribution, namely human retina and mouse bladder, were also demonstrated, suggesting potential for cross-domain transferability. This preliminary study suggests that deep learning generative models trained on OCT images from high-performance prototype systems may have potential in enhancing lower resolution data from mainstream/commercial systems, thereby bringing cutting-edge technology to the masses at low cost.

Construction of microneedle-assisted co-delivery platform and its combining photodynamic/immunotherapy.

Despite advances in photodynamic therapy (PDT) for treating superficial tumor, the prospect of this monotherapy remains challenges in the context of systemic phototoxicity and poor efficacy. In this work, a physiologically self-degradable microneedle (MN)-assisted platform is developed for combining PDT and immunotherapy via controlled co-delivery of photosensitizer (PS) and checkpoint inhibitor anti-CTLA4 antibody (aCTLA4), which generates synergistic reinforcement outcome while reducing side effects. MN is composed of biocompatible hyaluronic acid integrated with the pH-sensitive dextran nanoparticles, which is fabricated to simultaneously encapsulate hydrophobic (Zinc Phthalocyanine) and hydrophilic agents (aCTLA4) via a double emulsion method. This co-loading carrier can aggregate effectively around topical tumor by microneedle-assisted transdermal delivery. In vivo studies using 4T1 mouse models, PDT firstly exerts its effect to killing tumor and triggers the immune responses, subsequently, facilitating the immunotherapy with immune checkpoint inhibitor (aCTLA4). The possible mechanism and systemic effects of the combined therapy are investigated, which demonstrate that this co-administration platform can be a promising tool for focal cancer treatment.

Synthesis, antifungal activity and potential mechanism of fusidic acid derivatives possessing amino-terminal groups.

Aim: Fusidic acid (FA) is a narrow-spectrum bacteriostatic antibiotic. We inadvertently discovered that a FA derivative modified by an amino-terminal group at the 3-OH position, namely 2, inhibited the growth of Cryptococcus neoformans. Methods & results: Multiscale molecular modeling approaches were used to analyze the binding modes of 2 with eEF2. FA derivatives modified at the 3-OH position were designed based on in silico models; seven derivatives possessing different amino-terminal groups were synthesized and tested in vitro for antifungal activity against C. neoformans. Conclusion: Compound 7 had the strongest minimum inhibitory concentration. Two protonated nitrogen atoms of 7 interacted with a negative electrostatic pocket of eEF2 likely explain the superiority of 7-2.