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Stem cell regenerative medicine therapies have emerged as promising treatments for currently incurable diseases. A remaining challenge for cell therapies is the ability to track the migration and distribution of the transplanted cells in a long-term, noninvasive manner in vivo to assess their efficacy. This study develops a noninvasive, and high spatial resolution photoacoustic microscopy (PAM) and optical coherence tomography (OCT) imaging system for in vivo tracking of subretinally injected progenitor human retinal pigment epithelium cells (ARPE-19) labeled with chainlike gold nanoparticle (CGNP) clusters in RPE damage. CGNP provided significant PAM, OCT, and fluorescence signals to selectively track the migration of ARPE-19 cells in living rabbit eyes for 3 months. PAM and OCT imaging allow accurate anatomical information to determine the exact retinal layer in which the transplanted ARPE-19 cells are located which was confirmed by histology. This presents an efficient and advanced technology to visualize fundamental biological processes of cell therapies in complex in vivo environments in real time.

Background Infliximab (IFX) is the first-line treatment for patients with Crohn’s disease (CD) and is noted for its relatively high cost. The therapeutic efficacy of IFX has noticeable individual differences. Known single-gene polymorphisms (SNPs) are inadequate for predicting non-response to IFX. In this study, we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model. Methods In this retrospective study, we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019. Primary non-response (PNR) and non-durable response (NDR) were evaluated using a simple endoscopic score for CD (SES-CD). A total of 125 SNPs within 44 genes were genotyped. A multivariate logistic-regression model was established to predict non-response to IFX. An area-under-the-receiver-operating-characteristics curve (AUROC) was applied to evaluate the predictive model performance. Results Forty-two of 206 (20.4%) patients experienced PNR and 15 of 159 (9.4%) patients experienced NDR. Nine SNPs were associated with PNR (P Conclusion Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.

Objective: Photo-mediated ultrasound therapy (PUT) is a novel, non-invasive, agent-free, highly selective, and precise anti-vascular technique. PUT removes microvessels through promoting cavitation activity precisely in targeted microvessels by applying synchronized nanosecond laser pulses and ultrasound bursts. The synchronization between laser and ultrasound is critical to the outcome of PUT. Methods : Through theoretical simulation and experimental study, the effect of synchronization between laser pulses and ultrasound bursts on cavitation activity during PUT is evaluated. Results: By using a theoretical model, we found that cavitation activity was enhanced when laser pulses and ultrasound bursts were synchronized such that the produced photoacoustic wave overlaid the rarefactional phase of the ultrasound wave. This finding was then verified through in vitro studies where cavitation was monitored by using a passive cavitation detector. Furthermore, we demonstrated that the in vivo treatment outcome of PUT in rabbits was directly related to the synchronization between laser and ultrasound. The anti-vascular effect could only be observed when laser and ultrasound were properly synchronized in vivo . Conclusion: PUT is more efficient when the laser-induced photoacoustic wave overlays the rarefactional phase of the ultrasonic wave. Significance: This is a systematic study to investigate the synchronization effect of PUT, which would be significant for further understanding the mechanism and further improving the treatment efficiency of PUT.

BACKGROUND AND OBJECTIVES We have developed a novel anti-vascular technique, termed photo-mediated ultrasound therapy (PUT), which utilizes nanosecond duration laser pulses synchronized with ultrasound bursts to remove the microvasculature through cavitation. The objective of the current study is to explore the potential of PUT in removing subcutaneous microvessels. STUDY DESIGN/MATERIALS AND METHODS The auricular blood vessels of two New Zealand white rabbits were treated by PUT with a peak negative ultrasound pressure of 0.45 MPa at 0.5 MHz, and a laser fluence of 0.056 J/cm2 at 1064 nm for 10 minutes. Blood perfusion in the treated area was measured by a commercial laser speckle imaging (LSI) system before and immediately after treatment, as well as at 1 hour, 3 days, 2 weeks, and 4 weeks post-treatment. Perfusion rates of 38 individual vessels from four rabbit ears were tracked during this time period for longitudinal assessment. RESULTS The measured perfusion rates of the vessels in the treated areas, as quantified by the relative change in perfusion rate, showed a statistically significant decrease for all time points post-treatment (P

Previous exposure-response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure-response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B-cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The trough concentration in the first cycle (C1-trough ) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C1-trough and achieving a CR was confirmed by matched-pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C1-trough (≥18.40 μg/ml) was associated with longer progression-free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C1-trough less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C1-trough greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C1-trough , with 51.02% of patients at stage IV with an observed C1-trough less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m2 may help to improve clinical outcomes.

PURPOSE: Electron-based ultra-high dose rate radiation therapy (UHDR-RT), also known as Flash-RT, has shown the ability to improve the therapeutic index in comparison to conventional radiotherapy (CONV-RT) through increased sparing of normal tissue. However, the extremely high-dose rates in UHDR-RT have raised the need for accurate real-time dosimetry tools. This work aims to demonstrate the potential of the emerging technology of Ionized Radiation Acoustic Imaging (iRAI) through simulation studies and investigate its characteristics as a promising relative in vivo dosimetric tool for UHDR-RT. METHODS: The detection of induced acoustic waves following a single UHDR pulse of a modified 6 MeV 21EX Varian Clinac in a uniform porcine gelatin phantom that is brain-tissue equivalent was simulated for an ideal ultrasound transducer. The full 3D dose distributions in the phantom for a 1x1 cm(2) field were simulated using EGSnrc (BEAMnrc\DOSXYZnrc) Monte Carlo (MC) codes. The relative dosimetry simulations were verified with dose experimental measurements using Gafchromic films. The spatial dose distribution was converted into an initial pressure source spatial distribution using the medium dependent dose-pressure relation. The MATLAB based toolbox k-Wave was then used to model the propagation of acoustic waves through the phantom and perform time-reversal (TR) based imaging reconstruction. The effect of the various linear accelerator (linac) operating parameters, including linac pulse duration and pulse repetition rate (frequency), were investigated as well. RESULTS: The Monte Carlo dose simulation results agreed with the film measurement results, specifically at the central beam region up to 80% dose within approximately 5% relative error for the central profile region and a local relative error of < 6 % for percentage dose depth. IRAI-based FWHM of the radiation beam was within approximately 3 mm relative to the MC simulated beam FWHM at the beam entrance. The real time pressure signal change agreed with the dose changes proving the capability of the iRAI for predicting the beam position. IRAI was tested through 3D simulations of its response to be based on the temporal changes in the linac operating parameters on a dose per pulse basis as expected theoretically from the pressure-dose proportionality. The pressure signal amplitude obtained through 2D simulations was proportional to the dose per pulse. The instantaneous pressure signal amplitude decreases as the linac pulse duration increases, as predicted from the pressure wave generation equations, such that the shorter the linac pulse the higher the signal and the better the temporal (spatial) resolutions of iRAI. The effect of the longer linac pulse duration on the spatial resolution of the 3D constructed iRAI images was corrected for through linac pulse deconvolution. This correction has improved the passing rate of the 1%/1mm gamma test criteria, between the pressure-constructed and dosimetric beam characteristic, to as high as 98%. CONCLUSIONS: A full simulation workflow was developed for testing the effectiveness of iRAI as a promising relative dosimetry tool for UHDR-RT radiation therapy. IRAI has shown the advantage of 3D dose mapping through the dose signal linearity and hence has the potential to be a useful dosimeter at depth dose measurement and beam localization and hence potentially for in vivo dosimetry in UHDR-RT.

The photoacoustic (PA) technique is uniquely positioned for biomedical applications primarily due to its ability to visualize optical absorption contrast in deep tissue at ultrasound resolution. In this work, via both three-dimensional (3D) numerical simulations and in vivo experiments on human subjects, we investigated the possibility of PA measurement of human calcaneus bones in vivo in a non-invasive manner, as well as its feasibility to differentiate osteoporosis patients from normal subjects. The results from the simulations and the experiments both demonstrated that, when one side of the heel is illuminated by laser with light fluence under the ANSI safety limit, the PA signal generated in the human calcaneus bone can be detected by an ultrasonic transducer at the other side of the heel (i.e. transmission mode). Quantitative power spectral analyses of the calcaneus bone PA signals were also conducted, demonstrating that the microarchitectural changes in calcaneus bone due to osteoporosis can be detected, as reflected by enhanced high frequency components in detected PA bone signal. Further statistical analysis of the experimental results from 10 osteoporosis patients and 10 healthy volunteers showed that the weighted frequency as a quantified PA spectral parameter can differentiate the two subject groups with statistical significance.

INTRODUCTION Thiopurine S-methyltransferase (TPTM) is a well known biomarker for thiopurine-induced leucopenia, which has limited value in Asia. Instead, NUDT15 C415T is a promising predictor in Asia. AIMS To explore whether an optimised strategy based on NUDT15 C415T genotypes affects thiopurine-induced leucopenia, as well as efficacy in Chinese patients with Crohn's disease. METHODS Patients with Crohn's disease and indications for thiopurines were included from two hospitals in China. They were randomly assigned to either the intervention or the control group. In the intervention group, those with genotype CC received a standard dose (control group), those with CT genotype received 50% of the standard dose, those with TT genotype received alternative drugs. The primary endpoint was thiopurine-induced leucopenia (

Background Trough levels of the post-induction serum infliximab (IFX) are associated with short-term and long-term responses of Crohn’s disease patients to IFX, but the inter-individual differences are large. We aimed to elucidate whether single gene polymorphisms (SNPs) within FCGR3A, ATG16L1, C1orf106, OSM, OSMR, NF-κB1, IL1RN, and IL10 partially account for these differences and employed a multivariate regression model to predict patients’ post-induction IFX levels. Methods The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy. Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped. Associations between SNPs and IFX levels were analysed. Then, a multivariate logistic-regression model was developed to predict whether the patients’ IFX levels achieved the threshold of therapy (3 μg/mL). Results Six SNPs (rs7587051, rs143063741, rs442905, rs59457695, rs3213448, and rs3021094) were significantly associated with the post-induction IFX trough level (P = 0.015, P Conclusions Polymorphisms in C1orf106, IL1RN, and IL10 play an important role in the variability of IFX post-induction levels, as indicated in this multivariate prediction model of IFX levels with fair performance.

Background Thiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes? Aim To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes. Methods Patients' clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured. Results A total of 411 Crohn's disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively. Conclusion The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

Using data from a new hedge fund database, we examine the impact of social networks on the return comovement of stock hedge funds in China. We use structural holes in the college alumni networks of managers to measure the managers’ social network positions. We perform an empirical analysis on a sample of 3,012 hedge fund products in China from 2010 to 2017. We find that greater structural holes are associated with higher return comovement. The positive impact of the structural holes on return comovement is not affected by market cycles, a manager's major in college, or his or her abilities.

Vascularization of engineered constructs is required to integrate an implant within the host blood supply. The ability to noninvasively monitor neovascularization of an implanted construct is ultimately critical for translation. Laser speckle contrast analysis (LASCA), a widely used imaging technique within regenerative medicine, has high spatial resolution but offers limited imaging depth and is only sensitive to perfused blood vessels. As an emerging technology, photoacoustic (PA) imaging can provide centimeters of imaging depth and excellent sensitivity in vascular mapping. PA imaging in combination with conventional ultrasound (US) imaging offers a potential solution to this challenge in regenerative medicine. In this study, we used an LED-based PA-US dual system to image and monitor angiogenesis for 7 days in fibrin-based scaffolds subcutaneously implanted in mice. Scaffolds, with or without basic fibroblast growth factor (bFGF), were imaged on day 0 (i.e., postimplantation), 1, 3, and 7 with both LASCA and PA-US imaging systems. Quantified perfusion measured by LASCA and PA imaging were compared with histologically determined blood vessel density on day 7. Vessel density corroborated with changes in perfusion measured by both LASCA and PA. Unlike LASCA, PA imaging enabled delineation of differences in neovascularization in the upper and the lower regions of the scaffold. Overall, this study has demonstrated that PA imaging could be a noninvasive and highly sensitive method for monitoring vascularization at depth in regenerative applications. IMPACT STATEMENT: Noninvasive imaging techniques provide insight into physiology that is complementary to tissue morphology obtained by invasive histology. Optical imaging techniques, such as laser speckle contrast analysis, are used in vivo to longitudinally evaluate vascularization. Despite their high spatial resolution, these techniques have a limited imaging depth. In this study, we demonstrate how a dual LED-based photoacoustic (PA) and ultrasound system can delineate changes in perfusion at depth within scaffolds containing basic fibroblast growth factor. Perfusion changes detected by PA corroborated with vessel density. PA imaging could be a noninvasive and sensitive method for evaluating vascularization at depth in larger constructs.

Institutional economists believe that language, as an important informal institution, has a significant impact on economic activities. However, the study of language on corporate behavior is still ...

With the capability of assessing high resolution optical contrast in soft tissues, photoacoustic imaging (PAI) can offer valuable structural and functional information of human joints, and hold potential for diagnosis and treatment monitoring of inflammatory arthritis. Recent studies have demonstrated that PAI can map 2D and 3D morphology of the cartilage, synovium, vascularity, and bone tissue in human peripheral joints. Initial trials with patients affected by inflammatory arthritis have also suggested that PAI can detect the hemodynamic properties in articular tissues as well as their changes due to active inflammation. This review focuses on the recent progress in technical development of PAI for human musculoskeletal imaging and inflammation detection. PAI can provide non-invasive and non-ionizing serial measurements for monitoring of therapeutic interventions with the potential for higher sensitivity than existing imaging modalities such as ultrasound. However, further investigation is needed to validate the value of PAI in rheumatology clinical settings. Keywords: Photoacoustic tomography, Human joint, Inflammatory arthritis

Xanthine oxidase (XO) competes with thiopurine S‐methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6‐mercaptopurine (6‐MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. We also evaluated whether a relationship between XO activity and incidence of thiopurine‐induced adverse effects (AEs) existed. Clinical data and blood samples were collected from 140 IBD patients before receiving AZA/6‐MP therapy, and the erythrocyte XO activity was measured. The XO activities of all patients were 20.29 ± 4.43 U/g Hb. No sex difference in XO activity was observed (p = .728), and the XO activity showed no difference between the UC and CD patients (p = .082). AEs were observed in 41 (29.3%) patients including leukopenia (26, 18.57%), gastrointestinal intolerance (11, 7.86%), flu‐like symptom (5, 3.57%), alopecia (5, 3.57%), and hepatotoxicity (1, 0.71%). XO activity was significantly lower in the patients with AEs than in those without AEs (18.40 ± 3.73 vs. 21.07 ± 4.48 U/g Hb, p = .001), especially in the patients with leukopenia (18.29 ± 3.68 vs. 21.07 ± 4.48 U/g Hb, p = .004). However, no significant difference in XO activity was found between patients with and without other AEs. Decreased XO activity was observed in the patients who developed flu‐like symptoms (17.58 ± 3.50 U/g Hb) and alopecia (18.67 ± 2.91 U/g Hb) compared to those who did not, although the differences did not reach statistical significance. These findings suggested that patients with low XO expression might have a high risk of thiopurine‐induced toxicity., Xanthine oxidase (XO) competes with thiopurine S‐methyltransferase (TPMT) and hypoxanthine guanine phosphoribosyltransferase (HPRT) to metabolize azathioprine (AZA)/6‐mercaptopurine (6‐MP) in vivo. A retrospective investigation was performed to detect the activity of XO in thiopurine curative Chinese inflammatory bowel disease (IBD) patients. The relationship between XO activity and incidence of thiopurine‐induced adverse effects (AEs) existed was also evaluated. XO activity of 140 IBD patients was 20.29 ± 4.43 U/g Hb. The distribution is normal‐skew (Z = 0.675, p = .752). There was a negative correlation between XO activity and the overall incidence of AEs. Patients with low XO expression might have high risk of thiopurine‐induced toxicity.

Distinguishing between acute and chronic intestinal obstruction is essential for the treatment of Crohn's disease (CD). We have demonstrated the capability of spectroscopy photoacoustic (PA) imaging in quantifying hemoglobin and collagen changes. We also developed strain-PA imaging as a novel method for quantifying the intestinal stiffness, which is a mechanical marker of CD. In this study, we combined the spectroscopy and stiffness measurements using a catheter probe and examined the proposed approach in a rabbit model of CD in vivo. The quantitative accuracy of the imaging was validated by histology and micro-elastometry.

As a newly invented technology, ionizing radiation acoustic imaging (iRAI) provides a potential solution for in vivo dosimetry and real-time online monitoring of radiation beam position during external beam radiotherapy, including both conventional and FLASH radiotherapy. In this study, the dose resolution as low as 1% from a single pulse was achieved, demonstrating a clinically acceptable sensitivity of iRAI in mapping the dose deposition. The relative displacement of the radiation beam with respect to the target tissue can be visualized in real time by our clinically ready iRAI and ultrasound (US) dual-modality imaging system.

A new concept to achieve ultrasound-mediated hyperthermia (USHT) with the guidance of X-ray-induced radiation acoustic imaging (xRAI) is proposed. During radiation therapy of cancer patients, the received acoustic signals for xRAI can be used to correct the aberration caused by inhomogeneous acoustic property of human skull and provide guidance for focused ultrasound to achieve USHT with the same ultrasound array at the X-ray dose deposition area. To prove this concept, simulations with a human head model were made for both point targets and a tumor volume. The focused acoustic patterns with and without xRAI-based aberration correction were compared. The feasibility of this xRAI-guided USHT concept was further demonstrated by experimental studies using a human skull.

Photo-mediated ultrasound therapy (PUT) holds potential as a novel antivascular method. In this work, we applied PUT to precisely remove corneal neovascularization in a rabbit eye model. A stable corneal suture-induced corneal neovascularization model was established in rabbits. These rabbits were later treated by PUT or used as controls. The treatment outcomes were evaluated through red-free photography and fluorescein angiography along with histology and immunohistochemistry. The experimental results demonstrated that PUT shows promise in improving the management of eye diseases by delivering selective treatment to pathologic vessels with minimized side effects.

We have developed a novel anti-vascular technique, termed photo-mediated ultrasound therapy (PUT), which utilizes nanosecond duration laser pulses synchronized with ultrasound bursts to remove microvasculature through cavitation. In this work, via the experiments in a rabbit ear model in vivo, the feasibility of PUT in the treatment of cutaneous microvessels was explored. Both the short-term effects and the long-term effects up to 4 weeks post-treatment were quantitatively assessed by measuring the perfusion rates of the vessels after treatment, showing that a single PUT treatment could significantly reduce blood perfusion. With unique advantages such as low laser fluence as compared with photothermolysis and agent-free treatment as compared with PDT, PUT holds potential to be developed into a new tool for the treatment of cutaneous vascular lesions.

Early identification of the margins and location of choroidal neovascularization (CNV) is critical for the precise diagnosis and treatment of numerous neovascular eye diseases, including age-related macular degeneration (AMD). Integration of multimodal photoacoustic microscopy (PAM) and optical coherence tomography (OCT) imaging has been developed to complement the strengths of each modality. A major challenge remains in selectively distinguishing CNV from native microvasculature due to the high optical absorption of hemoglobin. To overcome such limitations, RGD targeting peptides conjugated with gold nanorods (GNR-RGD) was used as multimodal contrast agents to increase the sensitivity of PAM and OCT, allowing for enhanced visualization of CNV due to RGD’s selective binding to integrins in neovascularization. The ability of GNR-RGD enhanced PAM and OCT imaging was evaluated in three New Zealand White rabbits with CNV models. The CNV model was created at day 28 post laser-induced retinal vein occlusion. In vivo color fundus photography, fluorescein angiography, PAM, and OCT imaging was acquired before and after intravenous injection of 400 μL GNR-RGD at concentration of 5 mg/mL at days 1, 3, 5, 7, and 14. Longitudinal studies show that GNR accumulated at CNV sites and led the PAM and OCT signal increased by 27.2-fold in PAM and 171.4 % in OCT peaking at 48 h post-injection and decreased at day 14. Histological analysis, TUNEL assay, and liver and kidney function tests show no systemic toxicity of GNR in the retina or vital organs. The above approaches can provide a potential multimodal molecular imaging tool for precise evaluation of CNV in AMD and other neovascular diseases.

To eliminate the limited angle effect of photoacoustic imaging based on ultrasound linear array, spatially distributed ultrasound sensor array is applied. The accurate sensor array position determines the quality of the imaging results. We proposed two methods based on photoacoustic and ultrasound signals to enhance the imaging quality using a full-ring array. Photoacoustic signals are used to regress the position of each element sensor. In phantom study and mouse brain study, imaging results can yield details clearly with average error rate of less than 50 μm. The proposed methods can contribute to precise biomedical imaging in future application scenarios.

Photo-mediated ultrasound therapy (PUT) is a novel, non-invasive, and agent-free therapeutic technique that uses a combination of relatively low-intensity ultrasound bursts and nanosecond laser pulses to selectively and precisely remove highly optically absorptive targets. In this work, we developed an integrated ultrasound photoacoustic theranostic system (UPTS) by combining a ultrasound system (V1, Verasonics) with a pulsed laser system. The results from the ex vivo experiments in rabbit tissues demonstrated that UPTS, by working with appropriate laser wavelengths, can selectively remove tissues such as knee tendon and liver via the cavitation synergistically created by the ultrasound bursts and the laser pulses. Such a theranostic system can deliver effective PUT treatment to biological samples along with real-time monitoring by the integrated ultrasound and photoacoustic imaging.

Objective: With the growth of interest in different medical study on biological function, non-invasive photoacoustic imaging of biological tissue attracts the interests for researchers. To eliminate the limited angle effect of photoacoustic imaging based on ultrasound linear array, spatially distributed ultrasound sensor array is applied. The accurate sensor array position determines the quality of the imaging results. In this study, we proposed three methods based on photoacoustic and ultrasound signals to enhance the imaging quality using a 256-element full-ring array. Methods: Groups of photoacoustic and ultrasound signals are used to regress the position of each element sensor. Result: In phantom study and mouse brain study, photoacoustic imaging results can both yield details clearly with average error rate of less than 1% (50 $\mu \text{m}$ ). Conclusion: The performance of our three methods have proved that they can be potentially applied to other ultrasound-based medical imaging studies with unknown distributed positions of sensor array to enhance the imaging quality. Significance: The proposed methods can contribute to precise biomedical imaging with unknown distributed positions of sensor array in different application scenarios.

One key pathological characteristic of seronegative spondyloarthropathy (SpA) is inflammation at the insertion of tendons and ligaments into the bone (enthesitis).We explore the potential of the emerging photoacoustic (PA) imaging in diagnosis of SpA and review its feasibility in detecting SpA-associated Achilles tendon enthesitis.A light-emitting diode (LED)-based PA and ultrasound combined system was employed. The PA images, both along the long and the short axes of each Achilles tendon insertion region, were acquired at 850-nm wavelength, which is sensitive in depicting increased blood volume (i.e., hyperemia). To assess the hyperemia indicating enthesis inflammation, two parameters were quantified in the imaged tendons, including the average intensity and the density of the color pixels in the pseudo-color PA images. Ten SpA patients, all of which met Assessment of SpA International Society (ASAS) criteria for SpA and were found to have Achilles enthesitis by clinical exam according to a board-certified rheumatologist, were included in the study.The PA and Doppler ultrasound imaging of Achilles enthesitis resulting from these 10 SpA patients were compared to those from 10 healthy volunteers, leading to statistically significant differences (p 0.05) in the applied t-tests.This preliminary clinical study suggests that the LED-based PA imaging holds a promise for sensitive and objective assessment of SpA enthesitis in an outpatient setting of the rheumatology clinic.

Significance: One key pathological characteristic of seronegative spondyloarthropathy (SpA) is inflammation at the insertion of tendons and ligaments into the bone (enthesitis). Aim: We explore the potential of the emerging photoacoustic (PA) imaging in diagnosis of SpA and review its feasibility in detecting SpA-associated Achilles tendon enthesitis. Approach: A light-emitting diode (LED)-based PA and ultrasound combined system was employed. The PA images, both along the long and the short axes of each Achilles tendon insertion region, were acquired at 850-nm wavelength, which is sensitive in depicting increased blood volume (i.e., hyperemia). To assess the hyperemia indicating enthesis inflammation, two parameters were quantified in the imaged tendons, including the average intensity and the density of the color pixels in the pseudo-color PA images. Ten SpA patients, all of which met Assessment of SpA International Society (ASAS) criteria for SpA and were found to have Achilles enthesitis by clinical exam according to a board-certified rheumatologist, were included in the study. Results: The PA and Doppler ultrasound imaging of Achilles enthesitis resulting from these 10 SpA patients were compared to those from 10 healthy volunteers, leading to statistically significant differences (p

Purpose Corneal neovascularization (CNV) is the invasion of new blood vessels into the avascular cornea, leading to reduced corneal transparency and visual acuity, impaired vision, and even blindness. Current treatment options for CNV are limited. We developed a novel treatment method, termed photo-mediated ultrasound therapy (PUT), that combines laser and ultrasound, and we tested its feasibility for treating CNV in a rabbit model. Methods A suture-induced CNV model was established in New Zealand White rabbits, which were randomly divided into two groups: PUT and control. For the PUT group, the applied light fluence at the corneal surface was estimated to be 27 mJ/cm2 at 1064-nm wavelength with a pulse duration of 5 ns, and the ultrasound pressure applied on the cornea was 0.43 MPa at 0.5 MHz. The control group received no treatment. Red-free photography and fluorescein angiography were utilized to evaluate the efficiency of PUT. Safety was evaluated by histology and immunohistochemistry. For comparison with the PUT safety results, conventional laser photocoagulation (LP) treatment was performed with standard clinical parameters: 532-nm continuous-wave (CW) laser with 0.1-second pulse duration, 450-mW power, and 75-µm spot size. Results In the PUT group, only 1.8% ± 0.8% of the CNV remained 30 days after treatment. In contrast, 71.4% ± 7.2% of the CNV remained in the control group after 30 days. Safety evaluations showed that PUT did not cause any damage to the surrounding tissue. Conclusions These results demonstrate that PUT is capable of removing CNV safely and effectively in this rabbit model. Translational relevance PUT can remove CNV safely and effectively.

Purpose Intravitreal (IVT) injection of DL-alpha-aminoadipic acid (AAA) is a new animal model for retinal neovascularization (RNV) reported in rabbits. This study performs longitudinal multimodal imaging for up to 1 year to evaluate DL-AAA RNV in both New Zealand white (NZW) rabbits and Dutch-Belted pigmented (DBP) rabbits. Method Detailed characterization and quantification of this model were performed in these two strains in 32 eyes by optical coherence tomography (OCT), fundus photography, and fluorescein angiography (FA) for up to 16 weeks following DL-AAA administration in 32 eyes and up to 52 weeks in 5 eyes. H & E histology was also performed in these two strains 8 weeks after injection of DL-AAA. Result RNV was successfully generated using 50 μL 80 mM DL-AAA solution for DBP rabbits and 80 μL 80 mM DL-AAA for NZW rabbits. The incidence of persistent vascular leakage is 100% (15/15) for DBP rabbits and 70.6% (12/17) for NZW rabbits at 16 weeks. Complications with NZW rabbits ultimately decreased the efficiency in NZW rabbits to 58.8% (10/17) of NZW rabbits getting persistent (to 16 weeks) vascular leakage without ocular complications as compared with 100% (15/15) in DBP rabbits. Five eyes (2 DBP and 3 NZW) were selected from those demonstrating RNV at 16 weeks and were monitored for up to 52 weeks. All 5 demonstrated persistent RNV to 52 weeks. Quantification of the mean leakage area (MLA) in DBP rabbits is more accurate than in NZW rabbits since the reduced contrast between the leakage and background in NZW rabbits makes it more challenging to quantify. Conclusion DL-AAA can induce persistent and quantifiable RNV in both DBP and NZW rabbits. DBP rabbits have a higher success rate, lower required volume of DL-AAA, and more accurate method for quantification that could be more desirable.

PURPOSE FLASH radiotherapy (FLASH-RT) is a novel irradiation modality with ultra-high dose rates (>40 Gy/s) that have shown tremendous promise for its ability to enhance normal tissue sparing while maintaining comparable tumor cell eradication toconventional radiotherapy (CONV-RT). Due to its extremely high dose rates, clinical translation of FLASH-RT is hampered by risky delivery and current limitations in dosimetric devices, which cannot accurately measure, in real time, dose at deeper tissue. This work aims to investigate ionizing radiation acoustic imaging (iRAI) as a promising image-guidance modality for real-time deep tissue dose measurements during FLASH-RT. The underlying hypothesis is that iRAI can enable mapping of dose deposition with respect to surrounding tissue with a single linear accelerator (linac) pulse precision in real time. In this work, the relationship between iRAI signal response and deposited dose was investigated as well as the feasibility of using a proof-of-concept dual-modality imaging system of ultrasound and iRAI for treatment beam co-localization with respect to underlying anatomy. METHODS Two experimental setups were used to study the feasibility of iRAI for FLASH-RT using 6 MeV electrons from a modified Varian Clinac. First, experiments were conducted using a single element focused transducer to take a series of point measurements in a gelatin phantom, which was compared with independent dose measurements using GAFchromic film. Secondly, an ultrasound and iRAI dual-modality imaging system utilizing a phased array transducer was used to take coregistered two-dimensional (2D) iRAI signal amplitude images as well as ultrasound B-mode images, to map the dose deposition with respect to surrounding anatomy in an ex vivo rabbit liver model with a single linac pulse precision. RESULTS Using a single element transducer, iRAI measurements showed a highly linear relationship between the iRAI signal amplitude and the linac dose per pulse (r2 = 0.9998) with a repeatability precision of 1% and a dose resolution error

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration–response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1–3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix ® NLME TM . The first cycle trough concentration ( C 1-trough ) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C 1-trough was 13.60 μg/mL. Patients with grade 1/2 had significantly lower C 1-trough compared with grade 3 (12.21 μg/mL vs. 23.45 μg/mL, P

Photoacoustic microscopy (PAM) has significant potential as a promising diagnostic method for eye diseases and can provide anatomic and functional information of the retinal and choroidal vasculature. However, there are no FDA-approved PAM systems for ophthalmic imaging. In this study, a comprehensive safety evaluation was performed to evaluate the safety of PAM retinal imaging and whether PAM causes damage to retinal structure or function in rabbit eyes. 12 Dutch-Belted pigmented rabbits received photoacoustic imaging to 57% of the retinal surface area with a laser energy of 5% of the ANSI safety limit for five consecutive days and followed before imaging and 3 days, 1, 2, 3, and 4 weeks post imaging. Retinal morphologic analyses using slit lamp examination, fundus photography, red free, FA, FAF, ICGA, and OCT showed no retinal hemorrhage, edema, detachment, vascular abnormalities, or pigmentary abnormalities in the retina or choroid after PAM imaging. Full-field ERG analysis showed no significant difference in scotopic or photopic a- and b-wave amplitudes or implicit times between the control and experimental eyes over time (n = 6, P values > 0.05). Retinal ultrastructural evaluation using TEM showed normal structure of organelles and nuclei, and no significant loss of cells after PAM. TUNEL assay showed no evidence of cells apoptosis in retina. Retinal histopathology indicated that the architecture and thickness of the retinal layers was well preserved in all experimental eyes. A positive control at 500% of the ANSI limit demonstrated significant damage. The comprehensive retinal safety evaluation demonstrated no damage to retinal structure or function for 4 weeks after PAM imaging in rabbits.

This report describes a novel therapeutic technique called photo-mediated ultrasound therapy (PUT). PUT applies synchronized short pulse duration (nanosecond) laser and ultrasound burst on targeted tissue, offering high-precision localized treatment. PUT is based on controlled induction and promotion of micro-cavitation activity in the target tissue. PUT is able to safely and effectively treat retinal neovascularization in rabbits with persistent nonperfusion up to 4 weeks after PUT in the choroidal vasculature.Clinical Relevance- PUT can selectively remove retinal angiogenesis in clinically-relevant disease models in humansized eyes (rabbit) without damaging surrounding tissue.

Photoacoustic (PA) imaging has shown its capability of characterizing intestinal inflammation and fibrosis endoscopically. With the purpose of clinical translation, we developed an endoscopic probe integrating an intracardiac ultrasound array and an 800 µm side-firing fiber optic inside a medical balloon catheter. The catheter probe, when collapsed, fits to the instrument channel of a colonoscope and can inflate for acoustic coupling when positioned at the disease location inside intestine. The performance of the probe in assessing the disease conditions including inflammation, fibrosis and muscle hypertrophy is under investigation in rabbits in vivo. The imaging results are validated by histopathology.

Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients. The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton. In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406–32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219–24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib. Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

Background: The current study is aimed to examine the impact of pharmacokinetics and gene polymorphisms of enzymes involving in absorption, distribution, metabolism and excretion (ADME) on the efficacy of gefitinib in non-small cell lung cancer (NSCLC) patients. Methods: Eligible patients with indication of gefitinib treatment were prospectively enrolled in this study. Two peripheral blood samples at baseline and before cycle 2 day 1 were collected for the detection of single nucleotide polymorphisms (SNPs) of drug ADME enzymes and trough drug concentration (C trough ) at steady state. Thirteen SNPs were genotyped using the Sequenom Massarray system. C trough was determined by validated high-performance liquid chromatographic method with tandem mass spectrometric (LC-MS/MS). Results: Fifty-eight NSCLC patients were enrolled in this study. The median of C trough was 175ng/ mL (range from 47.8 to 470 ng/mL). The trough concentration was not associated with either objective response or progression free survival (PFS). C trough was significantly lower in CYP3A4 rs2242480 CC + CT genotype than in TT genotype (P=0.019) and in ABCG2 rs2231142 AA genotype than in AC + CC genotype (P=0.031). ABCB1 rs2032582 dominant model was significantly correlated with overall response rate (ORR) and patients with GG phenotype respond better than patients with GT + TT phenotypes (84.6% vs . 51.2%, P=0.032). ABCB1 rs10256836 recessive model was significantly correlated with PFS and patients with GG phenotype achieved longer PFS than patients with GC + CC phenotypes (17.40 vs . 10.33 months, P=0.040). Conclusions: The C trough of gefitinib was significantly different between CYP3A4 and ABCG2 genotypes, but not with the efficacy of gefitinib treatment. ABCB1 rs2032582 and rs10256836 polymorphisms were correlated treatment outcome. Polymorphisms analysis of ABCB1 could be a predictive biomarker for gefitinib treatment.

Port-wine stain (PWS) is categorized as a benign capillary vascular malformation, which is difficult to cure. In general, PWS appears on the face, but it can affect other areas of the body too. The affected skin surface may thicken slightly and develop an irregular, pebbled surface in adulthood. PWS’s cosmetic appearance causes substantial mental stress for the patients. Currently, characterization and treatment evaluation of PWS are generally conducted using physical examination and using imaging tools like digital camera, ultrasound imaging, dermoscopy, and tristimulus colorimeters. All these commonly used imaging techniques do not offer enough imaging depth and contrast required for the accurate evaluation of PWS. In this clinical pilot study, we demonstrated for the first time that LED-based photoacoustics can be used as a point-of-care tool for clinical evaluation and PDT-treatment monitoring of PWS disease.

Background: Gefitinib-induced rash is a sign of favorable outcomes for patients with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash, the more survival benefits obtained from gefitinib is still unknown, and as for the severe rash a risk factor prediction model is needed. Method: A total of 346 patients were enrolled in this study. Gefitinib/metabolites and 9 gene polymorphisms, were determined by pharmacometabolomic and pharmacogenomics methods in an exploratory cohort. External cohort patients were enrolled to validate this model. Findings: The survival for patients with rash were significantly higher than patients without rash (p=0.0002, p= 0.0089)，but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95%CI=2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95%CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95%CI = 2.067-72.465, p = 0.0087; GG vs CC, OR=5.103, 95%CI=1.032-33.938, p=0.061). This model was confirmed in validation cohort with an excellent predictive ability (AUC = 0.749, 95%CI = 0.710-0.951). Interpretation: Our finding demonstrated that patients developed any grade rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash. However, our model would require further validation in a biomarker-led trial. Trial Registration: This study was registered at ClinicalTrials.gov (NCT01994057). Funding Statement: This study was funded by the National Natural Science Foundation of China (Grant Nos. 81730103, 81320108027, 81573507, 81473283, 81173131 and 81973398), The National Key Research and Development Program (Grant Nos. 2017YFC0909303 and 2016YFC0905001), Guangdong Provincial Key Laboratory of Construction Foundation (Grant No. 2017B030314030), Science and Technology Program of Guangzhou（201607020031）, National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province (No. 2017B090903004) and the 111 project (Grant: B16047). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by Human Ethics of Sun Yat-sen University Cancer Center (B2013-038-1) and conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization.

Objective and Impact Statement . To study the feasibility of combined functional photoacoustic (PA) and quantitative ultrasound (US) for diagnosis of osteoporosis in vivo based on the detection of chemical and microarchitecture (BMA) information in calcaneus bone. Introduction . Clinically available X-ray or US technologies for the diagnosis of osteoporosis do not report important parameters such as chemical information and BMA. With unique advantages, including good sensitivity to molecular and metabolic properties, PA bone assessment techniques hold a great potential for clinical translation. Methods . By performing multiwavelength PA measurements, the chemical information in the human calcaneus bone, including mineral, lipid, oxygenated-hemoglobin, and deoxygenated-hemoglobin, were assessed. In parallel, by performing PA spectrum analysis, the BMA as an important bone physical property was quantified. An unpaired t -test and a two-way ANOVA test were conducted to compare the outcomes from the two subject groups. Results . Multiwavelength PA measurement is capable of assessing the relative contents of several chemical components in the trabecular bone in vivo , including both minerals and organic materials such as oxygenated-hemoglobin, deoxygenated-hemoglobin, and lipid, which are relevant to metabolic activities and bone health. In addition, PA measurements of BMA show good correlations ( R 2 up to 0.65) with DEXA. Both the chemical and microarchitectural measurements from PA techniques can differentiate the two subject groups. Conclusion . The results from this initial clinical study suggest that PA techniques, by providing additional chemical and microarchitecture information relevant to bone health, may lead to accurate and early diagnosis, as well as sensitive monitoring of the treatment of osteoporosis.

PURPOSE Transrectal ultrasound (TRUS)-guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer. TRUS biopsy involves tissue removal, and suffers from low core yield as well as high false negative rate. A less invasive and more accurate diagnostic procedure for prostate cancer is therefore highly desired. Combining the optical sensitivity and ultrasonic resolution to resolve the spatial distribution of the major molecular components in tissue, photoacoustic (PA) technology could be an alternative approach for the diagnosis of prostate cancer. The purpose of this study was to examine the feasibility of identifying aggressive prostate cancer using interstitial PA measurements. METHODS Seventeen patients with prebiopsy magnetic resonance imaging (MRI), TRUS biopsies, and planned prostatectomies were enrolled in this study. The interstitial PA measurements were achieved using our recently developed needle PA probe, which was inserted into the ex vivo prostates in the fashion of a biopsy needle. A total of 70 interstitial PA measurements were acquired. The PA measurements were quantified by a previously established PA physio-chemical analysis (PAPCA) method. The histology has confirmed the nonaggressive and aggressive cancerous conditions at the insertion locations. The diagnostic accuracy was also compared to that provided by the prebiopsy MRI. RESULTS The quantitative study shows significant differences between the individual parameters of the nonaggressive and the aggressive cancerous regions (P < 0.005). Multivariate analysis of the quantitative features achieved a diagnostic accuracy of 78.6% for differentiating nonaggressive and aggressive prostate cancer tissues. CONCLUSIONS The proposed procedure has shown promises in the diagnosis of aggressive prostate cancer.

Valproate (VPA) is a choice for the treatment of primary generalized epilepsies and partial epilepsies. Unfortunately, weight gain or obesity is one of the most frequent adverse effects of VPA treatment. Genetic factors were shown to be involved in the effect. The aim of this study was to investigate the association of selected single nucleotide polymorphisms (SNPs) of cluster of differentiation 36 (CD36) and peroxisome proliferator-activated receptor γ (PPARγ) with VPA-induced weight gain and obesity in epileptic patients. A total of 225 Chinese Han epilepsy patients receiving VPA treatment were recruited in the study. Height and weight for the calculation of body mass index (BMI) were measured at the initiation of VPA therapy and in the follow-up examination. A BMI of 25 kg/m2 or higher was defined as obesity on the basis of the World Health Organization (WHO) criteria for Asian populations. Four SNPs in CD36 (rs1194197, rs7807607) and PPARγ (rs10865710, rs2920502) were genotyped using the Sequenom® MassArray iPlex platform. About 19.6% of epileptic patients receiving VPA therapy were found to become obese. After covariate analysis of age, gender, sex, height, initial BMI, and VPA dosage, the CD36 rs1194197 C allele and rs7807607 T allele (OR, 0.31; 95%CI, 0.13–0.72; P = 0.009 and OR, 0.38; 95%CI; 0.18–0.83; P = 0.02, respectively) were identified as protective factors for VPA-induced obesity. The PPARγ rs10865710 C allele carriers were found to be less likely to suffer from VPA-induced obesity compared with GG genotype carriers (OR, 0.04; 95%CI, 0.01–0.12; P

Integrating surface plasmon resonance (SPR) devices upon single-mode fiber (SMF) end facets renders label-free sensing systems that have a simple dip-and-read configuration, a small form factor, high compatibility with fiber-optic techniques, and invasive testing capability. Such devices are not only low cost replacement of current equipments in centralized laboratories, but also highly desirable for opening paths to new applications of label-free optical sensing technologies, such as point-of-care immunological tests and intravascular ultrasound imaging. In this paper, we explain the requirements and challenges for such devices from the perspectives of biomolecule and ultrasound detection applications. In such a context, we review our recent work on SMF end-facet SPR cavities. This include a glue-and-strip fabrication method to transfer a nano-patterned thin gold film to the SMF end-facet with high yield, high quality and high alignment precision, the designs of distributed Bragg reflector (DBR) and distributed feedback (DFB) SPR cavities that couple efficiently with the SMF guided mode and reach quality factors of over 100, and the preliminary results for biomolecule interaction sensing and ultrasound detection. The particular advantages and potential values of these devices have been discussed, in terms of sensitivity, data reliability, reproducibility, bandwidth, etc.

Anastrozole is currently used as first-line treatment in locally advanced or metastatic breast cancer. A generic anastrozole tablet was developed to offer an alternative to the marketed tablet formulation. The aim of the current study was to evaluate the bioequivalence between the test and reference formulations of anastrozole in a single-dose, 2-period, 2-sequence crossover study with a 14-day washout interval. A total of 20 healthy male Chinese volunteers were enrolled and completed the study, after oral administration of a single dose of 1.0-mg test and reference formulations of anastrozole. The blood samples were collected at different times and were determined by a fully validated high-pressure liquid chromatography-tandem mass spectrometry method. The evaluated pharmacokinetic parameters, including Cmax , AUC0-t , and AUC0-∞ , were assessed for bioequivalence based on current guidelines. The observed pharmacokinetic parameters of anastrozole of the test drug were similar to those of the reference formulation. The 90% confidence intervals of test/reference ratios for Cmax , AUC0-t , and AUC0-∞ were within the bioequivalence acceptance range of 80%-125%. The results obtained from these healthy Chinese subjects in this study suggest that the test formulation of anastrozole 1.0-mg tablet is bioequivalent to the reference formulation (Arimidex 1.0-mg tablet).

Imatinib at 400 mg daily is the standard treatment for patients affected with CML and GIST. The intervariability in plasma concentration is very significant. In many reports, a good therapeutic effect is attributed to an adequate concentration of Imatinib. However, few studies have been conducted to investigate the association between plasma concentration and side effects. Besides, no upper concentration limit of Imatinib plasma concentration detection has been established. The correlation of Imatinib trough concentrations (Cmin) with adverse effects (AEs) was described here. Plasma samples were obtained from patients after 3 months treatment with Imatinib (steady state, n = 122). Liquid chromatography/ tandem mass spectrometry was used to determine the concentration of Imatinib and its metabolite NDI. The incidence of myelosuppression was increased significantly with the increased Imatinib trough plasma concentration. The plasma level of Imatinib and NDI in patients who developed myelosuppression are 1698.3 ± 598.6 ng/mL and 242.1 ng/mL, respectively, which were significantly higher than those in patients who did not (1327.2 ± 623.4 ng/mL, P = 1.75 × 10‐4; 206.3 ng/mL, P = 0.006). Estimated exposure thresholds of Imatinib and NDI were 1451.6 ng/mL with ROCAUC (95%CI) of 0.693 (0.597–0.789) and 207.1 ng/mL with ROCAUC (95%CI) of 0.646 (0.546–0.745), respectively. Multivariate regression confirmed the correlation of Imatinib Cmin with myelosuppression. Other side effects such as fluid retention and rash were not found to be correlated with Imatinib concentrations. These results suggest that trough concentration of Imatinib should be taken into consideration to increase the safety of Imatinib therapy in GIST patients.

By using our dual-modality system enabling simultaneous real-time ultrasound (US) and photoacoustic (PA) imaging of human peripheral joints, we explored the potential contribution of PA imaging modality to rheumatology clinic. By performing PA imaging at a single laser wavelength, the spatially distributed hemoglobin content reflecting the hyperemia in synovial tissue in metacarpophalangeal (MCP) joints of 16 patients were imaged, and compared to the results from 16 healthy controls. In addition, by performing PA imaging at two laser wavelengths, the spatially distributed hemoglobin oxygenation reflecting the hypoxia in inflammatory joints of 10 patients were imaged, and compared to the results from 10 healthy controls. The statistical analyses of the PA imaging results demonstrated significant differences (p

Neovascularization in the eye is a common disorder. Abnormal microvessels can develop in the cornea, retina, or choroid of the eye, leading to severe vision loss if left untreated. Current treatment methods carry disadvantages or side effects, such as drug-resistance or damage to the surrounding healthy tissues. By applying synchronized laser pulses and ultrasound bursts, we developed a technique, termed photo-mediated ultrasound therapy (PUT), as a localized antivascular method based on the enhanced cavitation mechanism. PUT takes advantage of the high native optical contrast between blood and surrounding tissues, and has the unique capability to self-target microvessels without damaging surrounding tissues. The technique utilizes nanosecond laser pulses, which is spatially and temporally synchronized with low duty-cycle ultrasound bursts of sub-MHz frequencies at the targeted microvessels. We have tested the feasibility of PUT on the removal of neovascularization in the cornea, retina and choroid in a rabbit eye model. We found that neovascularization in the eye could be greatly reduced after PUT, and the occlusion of microvessels could last up to 4 weeks. In conclusion, PUT holds significant promises as a non-invasive method to precisely remove microvessels in neurovascular eye diseases by more selectively treating vasculature with minimized side-effects.

Using a database of hedge funds in China, this paper examines the impact of limited attention by analysing the performance of hedge fund managers who are distracted by managing multiple funds simultaneously, or managerial multitasking. We perform an empirical analysis on a sample of 1031 hedge fund managers in China over the period from April 2010 to December 2017. We find that managers who multitask have lower returns, lower alpha, and lower overall performance. We investigate the impact of the switch from single-tasking to multitasking on the fund performance and our results support the attention distraction hypothesis, but not in favor of the effort diversion or synergy creation hypothesis. Moreover, we find that the practice of multitasking has a negative impact on fund performance during a bull market. Further, we find that multitasking managers have lower performance if they use multiple strategies in fund activities or serve on the management team at fund companies.

e21046 Background: Gefitinib-induced diarrhea can be severe, if not properly handled, and can result in severe dose reductions and treatment interruptions or discontinuation. However, the mechanism of gefitinib-induced diarrhea remains unclear. STAT6 promotes disruption of epithelial tight junction integrity, intestinal inflammation and allergic disorders in intestine. Therefore, we explored the correlation between variations in STAT6 and gefitinib-induced diarrhea in advanced non-small cell lung cancer (NSCLC) patients. Methods: A total of 160 advanced NSCLC patients carrying EGFR mutations were enrolled. 8 tag single nucleotide polymorphisms (SNP) in STAT6, including rs10876963, rs167769, rs3122929, rs3024975, rs841718, rs324013, rs324015 and rs703817, were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. The associations between tag SNPs of STAT6 and diarrhea were analyzed by Chi square test and multivariate logistic regression. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: 71 patients (44.4%) suffered at least grade 1 gefitinib-induced diarrhea. We found rs167769 was associated with gefitinib- induced diarrhea in NSCLC patients. STAT6 rs167769 TT carriers were all suffering from gefitinib-induced diarrhea (OR = 2.4*1010, p = 0.999). Patients with STAT6 rs167769 TT have higher risk of developing severe (grade ≥ 2) diarrhea than those with STAT6 rs167769 CC/CT. Conclusions: STAT6 rs167769 is a predictive biomarker for gefitinib-induced diarrhea and the analysis of polymorphisms of STAT6 rs167769 might be beneficial to optimize gefitinib treatment. Further studies are needed to clarify the underlying mechanisms. Clinical trial information: NCT01994057.

e21041 Background: Gefitinib is first-line therapy for patients with EGFR-activating mutation in non-small cell lung cancer (NSCLC). Meanwhile, ̃30% patients were progression within 12 months even harboring EGFR-activating mutation. Furthermore, integrative scoring models for prediction of gefitinib outcomes are still lacking. Variations in genes of DNA repair and cell cycle pathway may have potential impacts on proliferation, migration and invasion of tumor cells. Therefore, we investigated a series of single nucleotide polymorphisms (SNP) in DNA repair and cell cycle genes based on an efficient algorithm machine learning algorithm for establishing an integrative scoring system for survival prediction following gefitinib therapy in NSCLC patients. Methods: A total of 282 patients with activating EGFR mutations were enrolled and divided into train cohort and test cohort, randomly. 125 SNPs in 47 candidate genes were selected by Heploview 4.2 and sequenced by Agena MassARRAY System. Predictive features were selected by randomForestSRC, an efficient algorithm machine learning algorithm to analyze survival data, for PFS following gefitinib therapy. The top candidate variables were presented into COX regression models with hazard ratio as weight for each predictor (HR = 1-1.49 = 1; HR = 1.5-2.49 = 2; HR = 2.5-3.49 = 3), providing p < 0.1. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: The progression risk predictive model was established by random forest survival and validated by COX regression analysis, included XRCC1 rs3213263(CT vs CC, RR = 1.997, 95%CI = 1.314-3.036, p = 0.001), FOXO3 rs75544369(GA vs GG, RR = 1.942, 95%CI = 1.139-3.309, p = 0.012), FOXM1 rs2302257(CC vs GG, RR = 2.889, 95%CI = 1.477-5.691, p = 0.002) and ERCC1 rs10408989(TT vs GT, RR = 1.735, 95%CI = 1.152-2.613, p = 0.008; GG vs GT, RR = 3.788, 95%CI = 1.625-8.832, p = 0.002). The progression risk score ranged from 0-10. 49 patients (25.52%) and 20 patients (22.22%) were scored 0, 18(9.38%) and 10(11.11%) patients were scored more than 5 in train cohort and test cohort, respectively. According to the risk score of patients, we divided the patients into four groups, the median PFS were 26.23(95%CI:14.23-35.37), 16.80(95%CI:12.87-23.60), 11.13(95%CI:8.87-16.70) and 6.25 (95% CI:4.43-11.67) months for 0, 2, 3&4 and ≥5 group (p < 0.0001) in the train cohort. Meanwhile, the median PFS were 18.80(95%CI:11.80-64.53),13.60(95%CI:9.17-27.33), 13.47(95%CI:9.83-18.40), 13.47(95%CI:9.83-18.40) and 7.40(95%CI:3.33- NA) months for 0, 2, 3&4 and ≥5 group in validation cohort (p = 0.0017). Conclusions: The risk score system is a simple tool for risk stratification in patients undergoing gefitinib. Widespread application of the score system will require further independent validation.