Dual-modal Photoacoustic and Ultrasound Imaging: from preclinical to clinical applications.

Photoacoustic imaging is a novel biomedical imaging modality that has emerged over the recent decades. Due to the conversion of optical energy into the acoustic wave, photoacoustic imaging offers high-resolution imaging in depth beyond the optical diffusion limit. Photoacoustic imaging is frequently used in conjunction with ultrasound as a hybrid modality. The combination enables the acquisition of both optical and acoustic contrasts of tissue, providing functional, structural, molecular, and vascular information within the same field of view. In this review, we first described the principles of various photoacoustic and ultrasound imaging techniques and then classified the dual-modal imaging systems based on their preclinical and clinical imaging applications. The advantages of dual-modal imaging were thoroughly analyzed. Finally, the review ends with a critical discussion of existing developments and a look toward the future.

Complement-Mediated Thrombotic Microangiopathy in a Patient With Antiphospholipid Syndrome and Anti-glomerular Basement Membrane Antibodies.

Thrombotic microangiopathy (TMA) is a range of diseases characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ injury. Complement-mediated TMA is a rare, life-threatening subtype of TMA that occurs due to the uncontrolled activation of the alternative complement pathway in the absence of normal regulation, often resulting from deficiencies of various regulatory proteins. Anti-glomerular basement membrane (anti-GBM) disease, previously known as Goodpasture syndrome, is a life-threatening form of vasculitis in which immunoglobulin G autoantibodies bind to the alpha-3 chain of type IV collagen in alveolar and glomerular basement membranes. We present the case of a patient with a history of antiphospholipid syndrome who was diagnosed with complement-mediated TMA during hospital admission for elevated anti-GBM antibody titers discovered during an outpatient evaluation for elevated creatinine levels. Upon admission, treatment was started for presumed anti-GBM disease, including high-dose intravenous methylprednisolone injections and multiple plasmapheresis sessions. However, renal biopsy results showed no evidence of anti-GBM disease, but rather evidence of TMA. Subsequent laboratory studies revealed decreased complement levels, suggestive of a diagnosis of complement-mediated TMA. The patient was started on rituximab and eculizumab infusions, and she was discharged in stable condition after a 15-day hospitalization with outpatient appointments scheduled for genetic testing and further infusions. This case illustrates the importance of recognizing the key clinical and diagnostic features of complement-mediated TMA to promptly initiate appropriate therapy.

Volumetric tri-modal imaging with combined photoacoustic, ultrasound, and shear wave elastography.

Photoacoustic imaging is a hybrid imaging approach that combines the advantages of optical and ultrasonic imaging in one modality. However, for comprehensive tissue characterization, optical contrast alone is not always sufficient. In this study, we combined photoacoustic imaging with high-resolution ultrasound and shear wave elastography. The multi-modal system can calculate optical absorption, acoustic reflection, and stiffness volumetrically. We constructed a multi-modal phantom with contrast for each imaging modality to test the system's performance. Experimental results indicate that the system successfully visualizes the embedded structures. We envision that the system will lead to more comprehensive tissue characterization for cancer screening and diagnosis.

Deep-E: A Fully-Dense Neural Network for Improving the Elevation Resolution in Linear-Array-Based Photoacoustic Tomography.

Linear-array-based photoacoustic tomography has shown broad applications in biomedical research and preclinical imaging. However, the elevational resolution of a linear array is fundamentally limited due to the weak cylindrical focus of the transducer element. While several methods have been proposed to address this issue, they have all handled the problem in a less time-efficient way. In this work, we propose to improve the elevational resolution of a linear array through Deep-E, a fully dense neural network based on U-net. Deep-E exhibits high computational efficiency by converting the three-dimensional problem into a two-dimension problem: it focused on training a model to enhance the resolution along elevational direction by only using the 2D slices in the axial and elevational plane and thereby reducing the computational burden in simulation and training. We demonstrated the efficacy of Deep-E using various datasets, including simulation, phantom, and human subject results. We found that Deep-E could improve elevational resolution by at least four times and recover the object's true size. We envision that Deep-E will have a significant impact in linear-array-based photoacoustic imaging studies by providing high-speed and high-resolution image enhancement.

Second-Generation Dual Scan Mammoscope With Photoacoustic, Ultrasound, and Elastographic Imaging Capabilities.

We recently developed the photoacoustic dual-scan mammoscope (DSM), a system that images the patient in standing pose analog to X-ray mammography. The system simultaneously acquires three-dimensional photoacoustic and ultrasound (US) images of the mildly compressed breast. Here, we describe a second-generation DSM (DSM-2) system that offers a larger field of view, better system stability, higher ultrasound imaging quality, and the ability to quantify tissue mechanical properties. In the new system, we doubled the field of view through laterally shifted round-trip scanning. This new design allows coverage of the entire breast tissue. We also adapted precisely machined holders for the transducer-fiber bundle sets. The new holder increased the mechanical stability and facilitated image registration from the top and bottom scanners. The quality of the US image is improved by increasing the firing voltage and the number of firing angles. Finally, we incorporated quasi-static ultrasound elastography to allow comprehensive characterization of breast tissue. The performance of the new system was demonstrated through in vivo human imaging experiments. The experimental results confirmed the capability of the DSM-2 system as a powerful tool for breast imaging.

Photoacoustic dual-scan mammoscope: results from 38 patients.

We have developed a photoacoustics-based imaging system, the dual-scan mammoscope (DSM), that combines optical contrasts with acoustic detection, to obtain the angiographic features in human breast. In this study, we investigated whether the system can differentiate malignant tumor and healthy breast. We have imaged 38 patients with various tumor types and compared results of tumor-bearing breast with healthy breast for each patient. We also compared the photoacoustic and ultrasound imaging results with clinical US. Vascular features in and around the tumor mass were visualized. We found that tumor-bearing breast contained vessels of larger caliber and exhibited stronger variations in the background signals than those in the contralateral healthy breasts. Preliminary data on photoacoustic and ultrasound images also indicate that the technique has potential in differentiating different tumor types. Overall, our results indicate that combining photoacoustic and ultrasound images can improve breast cancer screening.

Combination Chemo-Immunotherapy for Pancreatic Cancer Using the Immunogenic Effects of an Irinotecan Silicasome Nanocarrier Plus Anti-PD-1.

There is an urgent need to develop new life-prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo-immunotherapy response in an orthotopic Kras-dependent pancreatic cancer model. This discovery is premised on the weak-basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death-ligand 1 (PD-L1) expression. ICD is characterized by calreticulin expression and high-mobility group box 1 (HMGB1) release in dying Kras-induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti-PD-1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD-L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo-immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti-PD-1 leads to significantly enhanced survival improvement, and is far superior to anti-PD-1 plus either free irinotecan or Onivyde.

Development of Facile and Versatile Platinum Drug Delivering Silicasome Nanocarriers for Efficient Pancreatic Cancer Chemo-Immunotherapy.

In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high-dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak-basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2-diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras-derived pancreatic cancer (PDAC) model is demonstrated. Not only does IV injection of the DACHPt silicasome provide more efficacious cytotoxic tumor cell killing, but can also demonstrate that chemotherapy-induced cell death is accompanied by the features of immunogenic cell death (ICD) as well as a dramatic reduction in bone marrow toxicity. The added ICD features are reflected by calreticulin and high-mobility group box 1 expression, along with increased CD8+ /FoxP3+ T-cell ratios and evidence of perforin and granzyme B release at the tumor site. Subsequent performance of a survival experiment, demonstrates that the DACHPt silicasome generates a significant improvement in survival outcome, which can be extended by delayed administration of the anti-PD-1 antibody.

Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC) cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a liposome) was introduced to provide encapsulated irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace irinotecan in FOLFIRINOX, the liposomal formulation is currently prescribed as a second-line treatment option (in combination with 5-fluorouracil and leucovorin) for patients with metastatic PDAC who failed gemcitabine therapy. However, the toxicity of Onivyde remains a concern that needs to be addressed for use in CRC as well. Our goal was to custom design a mesoporous silica nanoparticle (MSNP) carrier for encapsulated irinotecan delivery in a robust CRC model. This was achieved by developing an orthotopic tumor chunk model in immunocompetent mice. With a view to increase the production volume and to expand the disease applications, the carrier design was improved by using an ethanol exchange method for coating of a supported lipid bilayer (LB) that entraps a protonating agent. The encapsulated protonating agent was subsequently used for remote loading of irinotecan. The excellent irinotecan loading capacity and stability of the LB-coated MSNP carrier, also known as a "silicasome", previously showed improved efficacy and reduced toxicity when compared to an in-house liposomal carrier in a PDAC model. Intravenous injection of the silicasomes in a well-developed orthotopic colon cancer model in mice demonstrated improved pharmacokinetics and tumor drug content over free drug and Onivyde. Moreover, improved drug delivery was accompanied by substantially improved efficacy, increased survival, and reduced bone marrow and GI toxicity compared to the free drug and Onivyde. We also confirmed that the custom-designed irinotecan silicasomes outperform Onivyde in an orthotopic PDAC model. In summary, the Ir-silicasome appears to be promising as a treatment option for CRC in humans based on improved efficacy and the carrier's favorable safety profile.

Can technology really help to reduce underage drinking? New evidence on the effects of false ID laws with scanner provisions.

In Volume 36 of this journal, Yoruk (2014) uses data from the National Longitudinal Survey of Youth 1997 and finds that false ID laws with scanner provisions have large impacts on binge drinking participation, frequency of alcohol consumption and binge drinking frequency among minors. This paper reexamines how false ID laws with scanner provisions affect underage drinking. I first demonstrate that analyses based on NLSY97 data fail falsification exercises testing for significant pre-intervention effects, and that the estimated effects based on these data are highly sensitive to the inclusion of a lead term and to sample selection, which weakens confidence in the large estimated effects reported in Yoruk (2014). I then use data from the Youth Risk Behavior Surveillance System to show that false ID laws with scanner provisions have no effect on underage drinking behavior.

Testing Separability and Independence of Perceptual Dimensions with General Recognition Theory: A Tutorial and New R Package (grtools).

Determining whether perceptual properties are processed independently is an important goal in perceptual science, and tools to test independence should be widely available to experimental researchers. The best analytical tools to test for perceptual independence are provided by General Recognition Theory (GRT), a multidimensional extension of signal detection theory. Unfortunately, there is currently a lack of software implementing GRT analyses that is ready-to-use by experimental psychologists and neuroscientists with little training in computational modeling. This paper presents grtools, an R package developed with the explicit aim of providing experimentalists with the ability to perform full GRT analyses using only a couple of command lines. We describe the software and provide a practical tutorial on how to perform each of the analyses available in grtools. We also provide advice to researchers on best practices for experimental design and interpretation of results when applying GRT and grtools.

Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxan fragment as a novel class of potent methionine aminopeptidase type II inhibitors.

A series of 1,2,4-triazole derivatives containing 1,4-benzodioxan (5a-5q) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential MetAP2 inhibitors. All the synthesized compounds were first reported. Among the compounds, compound 5k showed the most potent biological activity against HEPG2 cancer cell line (IC(50)=0.81 µM for HEPG2 and IC(50)=0.93 µM for MetAP2), which was comparable to the positive control. Docking simulation by positioning compound 5k into the MetAP2 structure active site was performed to explore the possible binding model. The results of apoptosis and Western-blot assay demonstrated that compound 5k possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 5k with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell.