TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer.

Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2+ mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2+ mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.

Ultra-fast dynamic line-field optical coherence elastography.

In this work, we present an ultra-fast line-field optical coherence elastography system (LF-OCE) with an 11.5 MHz equivalent A-line rate. The system was composed of a line-field spectral domain optical coherence tomography system based on a supercontinuum light source, Michelson-type interferometer, and a high-speed 2D spectrometer. The system performed ultra-fast imaging of elastic waves in tissue-mimicking phantoms of various elasticities. The results corroborated well with mechanical testing. Following validation, LF-OCE measurements were made in in situ and in in vivo rabbit corneas under various conditions. The results show the capability of the system to rapidly image elastic waves in tissues.

Confocal air-coupled ultrasonic optical coherence elastography probe for quantitative biomechanics.

We present an air-coupled ultrasonic radiation force probe co-focused with a phase-sensitive optical coherence tomography (OCT) system for quantitative wave-based elastography. A custom-made 1 MHz spherically focused piezoelectric transducer with a concentric 10 mm wide circular opening allowed for confocal micro-excitation of waves and phase-sensitive OCT imaging. Phantom studies demonstrated the capabilities of this probe to produce quasi-harmonic excitation up to 4 kHz for generation of elastic waves. Experimental results in ocular tissues showed highly detailed 2D and 3D elasticity mapping using this approach with great potential for clinical translation.

Nanobomb optical coherence elastography.

Wave-based optical elastography is rapidly emerging as a powerful technique for quantifying tissue biomechanical properties due to its noninvasive nature and high displacement sensitivity. However, current approaches are limited in their ability to produce high-frequency waves and highly localized mechanical stress. In this Letter, we demonstrate that the rapid liquid-to-gas phase transition of dye-loaded perfluorocarbon nanodroplets ("nanobombs") initiated by a pulsed laser can produce highly localized, high-frequency, and broadband elastic waves. The waves were detected by an ultra-fast line-field low-coherence holography system. For comparison, we also excited waves using a focused micro-air-pulse. Results from tissue-mimicking phantoms showed that the nanobombs produced elastic waves with frequencies up to ∼9 kHz, which was much greater than the ∼2 kHz waves excited by the air-pulse. Consequently, the nanobombs enabled more accurate quantification of sample viscoelasticity. Combined with their potential for functionalization, the nanobombs show promise for accurate and highly specific noncontact all-optical elastography.

Noncontact Elastic Wave Imaging Optical Coherence Elastography for Evaluating Changes in Corneal Elasticity Due to Crosslinking.

The mechanical properties of tissues can provide valuable information about tissue integrity and health and can assist in detecting and monitoring the progression of diseases such as keratoconus. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess localized mechanical contrast in tissues with micrometer spatial resolution. In this work we present a noncontact method of optical coherence elastography to evaluate the changes in the mechanical properties of the cornea after UV-induced collagen cross-linking. A focused air-pulse induced a low amplitude (µm scale) elastic wave, which then propagated radially and was imaged in three dimensions by a phase-stabilized swept source optical coherence tomography (PhS-SSOCT) system. The elastic wave velocity was translated to Young's modulus in agar phantoms of various concentrations. Additionally, the speed of the elastic wave significantly changed in porcine cornea before and after UV-induced corneal collagen cross-linking (CXL). Moreover, different layers of the cornea, such as the anterior stroma, posterior stroma, and inner region, could be discerned from the phase velocities of the elastic wave. Therefore, because of noncontact excitation and imaging, this method may be useful for in vivo detection of ocular diseases such as keratoconus and evaluation of therapeutic interventions such as CXL.

Phase-sensitive optical coherence elastography at 1.5 million A-Lines per second.

Shear-wave imaging optical coherence elastography (SWI-OCE) is an emerging method for 3D quantitative assessment of tissue local mechanical properties based on imaging and analysis of elastic wave propagation. Current methods for SWI-OCE involve multiple temporal optical coherence tomography scans (M-mode) at different spatial locations across tissue surface (B- and C-modes). This requires an excitation for each measurement position leading to clinically unacceptable long acquisition times up to tens of minutes. In this Letter, we demonstrate, for the first time, noncontact true kilohertz frame-rate OCE by combining a Fourier domain mode-locked swept source laser with an A-scan rate of ∼1.5 MHz and a focused air-pulse as an elastic wave excitation source. The propagation of the elastic wave in the sample was imaged at a frame rate of ∼7.3 kHz. Therefore, to quantify the elastic wave propagation velocity in a single direction, only a single excitation was needed. This method was validated by quantifying the elasticity of tissue-mimicking agar phantoms as well as of a porcine cornea ex vivo at different intraocular pressures. The results demonstrate that this method can reduce the acquisition time of an elastogram to milliseconds.

Optical coherence elastography measures the biomechanical properties of the ex vivo porcine cornea after LASIK.

Significance: The biomechanical impact of refractive surgery has long been an area of investigation. Changes to the cornea structure cause alterations to its mechanical integrity, but few studies have examined its specific mechanical impact. Aim: To quantify how the biomechanical properties of the cornea are altered by laser assisted in situ keratomileusis (LASIK) using optical coherence elastography (OCE) in ex vivo porcine corneas. Approach: Three OCE techniques, wave-based air-coupled ultrasound (ACUS) OCE, heartbeat (Hb) OCE, and compression OCE were used to measure the mechanical properties of paired porcine corneas, where one eye of the pair was left untreated, and the fellow eye underwent LASIK. Changes in stiffness as a function of intraocular pressure (IOP) before and after LASIK were measured using each technique. Results: ACUS-OCE showed that corneal stiffness changed as a function of IOP for both the untreated and the treated groups. The elastic wave speed after LASIK was lower than before LASIK. Hb-OCE and compression OCE showed regional changes in corneal strain after LASIK, where the absolute strain difference between the cornea anterior and posterior increased after LASIK. Conclusions: The results of this study suggest that LASIK may soften the cornea and that these changes are largely localized to the region where the surgery was performed.

A new approach used in docking study for predicting the combination drug efficacy in EML4-ALK target of NSCLC.

Combination drug treatments are usually used in many diseases, including cancers and AIDS. This treatment strategy is known as one of the cornerstone in therapies, which potentially reduces drug toxicity and drug resistance and also enhances therapeutic efficacy. Before using a drug in treatment, several experimental studies are done in vivo and in vitro to ensure the drug's efficacy. In such experimental studies, the drug's efficacy is evaluated with the help of drug dose ratio. In the combination drug experimental studies, the efficacy of the drugs is quantified with the Combination Index (CI) value and then interpreted by various terminologies like synergy, additive, and antagonism. Several computational models have now been invented for the speedy identification of combination drug efficacy. Unfortunately, none of these models have predicted the atomic level interaction of the combination drug with the target protein. This type of intermolecular interaction can be identified with the help of docking software. In the proposed work, we try to identify the intermolecular interaction and efficacy of the combination drug Crzizotinib and Temozolomide in the target of EML4-ALK in NSCLC by in silico study. The result of the study was evaluated with drug properties and Complex Energy (CE) of the docked complex rather than using docking score and binding energy. From this study, we could understand that first, Crizotinib and then after the Temozolomide drug binded on the EML4-ALK protein complex, showed very least CE and also identified that the combination of Crizotinib and Temozolomide drug are more effective in NSCLC.Communicated by Ramaswamy H. Sarma.

Integrated ACMG-approved genes and ICD codes for the translational research and precision medicine.

A timely understanding of the biological secrets of complex diseases will ultimately benefit millions of individuals by reducing the high risks for mortality and improving the quality of life with personalized diagnoses and treatments. Due to the advancements in sequencing technologies and reduced cost, genomics data are developing at an unmatched pace and levels to foster translational research and precision medicine. Over 10 million genomics datasets have been produced and publicly shared in 2022. Diverse and high-volume genomics and clinical data have the potential to broaden the scope of biological discoveries and insights by extracting, analyzing and interpreting the hidden information. However, the current and still unresolved challenges include the integration of genomic profiles of the patients with their medical records. The definition of disease in genomics medicine is simplified, whereas in the clinical world, diseases are classified, identified and adopted with their International Classification of Diseases (ICD) codes, which are maintained by the World Health Organization. Several biological databases have been produced, which include information about human genes and related diseases. However, still, there is no database that exists, which can precisely link clinical codes with relevant genes and variants to support genomic and clinical data integration for clinical and translational medicine. In this project, we focused on the development of an annotated gene-disease-code database, which is accessible through an online, cross-platform and user-friendly application, i.e. PROMIS-APP-SUITE-Gene-Disease-Code. However, our scope is limited to the integration of ICD-9 and ICD-10 codes with the list of genes approved by the American College of Medical Genetics and Genomics. The results include over 17 000 diseases and 4000 ICD codes, and over 11 000 gene-disease-code combinations. Database URL https://promis.rutgers.edu/pas/.

Multimodal Heartbeat and Compression Optical Coherence Elastography for Mapping Corneal Biomechanics.

The biomechanical properties of the cornea have a profound influence on the health, structural integrity, and function of the eye. Understanding these properties may be critical for diagnosis and identifying disease pathogenesis. This work demonstrates how two different elastography techniques can be combined for a multimodal approach to measuring corneal biomechanical properties. Heartbeat optical coherence elastography (Hb-OCE) and compression OCE were performed simultaneously to measure the stiffness of the cornea in an in vivo rabbit model. Measurements were further performed after collagen crosslinking to demonstrate how the combined technique can be used to measure changes in corneal stiffness and map mechanical contrast. The results of this work further suggest that measurements from Hb-OCE and compression OCE are comparable, meaning that Hb-OCE and compression OCE may be used interchangeably despite distinct differences in both techniques.

In vivo assessment of corneal biomechanics under a localized cross-linking treatment using confocal air-coupled optical coherence elastography.

The localized application of the riboflavin/UV-A collagen cross-linking (UV-CXL) corneal treatment has been proposed to concentrate the stiffening process only in the compromised regions of the cornea by limiting the epithelium removal and irradiation area. However, current clinical screening devices dedicated to measuring corneal biomechanics cannot provide maps nor spatial-dependent changes of elasticity in corneas when treated locally with UV-CXL. In this study, we leverage our previously reported confocal air-coupled ultrasonic optical coherence elastography (ACUS-OCE) probe to study local changes of corneal elasticity in three cases: untreated, half-CXL-treated, and full-CXL-treated in vivo rabbit corneas (n = 8). We found a significant increase of the shear modulus in the half-treated (>450%) and full-treated (>650%) corneal regions when compared to the non-treated cases. Therefore, the ACUS-OCE technology possesses a great potential in detecting spatially-dependent mechanical properties of the cornea at multiple meridians and generating elastography maps that are clinically relevant for patient-specific treatment planning and monitoring of UV-CXL procedures.

Multiple Optical Elastography Techniques Reveal the Regulation of Corneal Stiffness by Collagen XII.

Purpose: Collagen XII plays a role in regulating the structure and mechanical properties of the cornea. In this work, several optical elastography techniques were used to investigate the effect of collagen XII deficiency on the stiffness of the murine cornea. Methods: A three-prong optical elastography approach was used to investigate the mechanical properties of the cornea. Brillouin microscopy, air-coupled ultrasonic optical coherence elastography (OCE) and heartbeat OCE were used to assess the mechanical properties of wild type (WT) and collagen XII-deficient (Col12a1-/-) murine corneas. The Brillouin frequency shift, elastic wave speed, and compressive strain were all measured as a function of intraocular pressure (IOP). Results: All three optical elastography modalities measured a significantly decreased stiffness in the Col12a1-/- compared to the WT (P < 0.01 for all three modalities). The optical coherence elastography techniques showed that mean stiffness increased as a function of IOP; however, Brillouin microscopy showed no discernable trend in Brillouin frequency shift as a function of IOP. Conclusions: Our approach suggests that the absence of collagen XII significantly softens the cornea. Although both optical coherence elastography techniques showed an expected increase in corneal stiffness as a function of IOP, Brillouin microscopy did not show such a relationship, suggesting that the Brillouin longitudinal modulus may not be affected by changes in IOP. Future work will focus on multimodal biomechanical models, evaluating the effects of other collagen types on corneal stiffness, and in vivo measurements.

Artificial Intelligence, Healthcare, Clinical Genomics, and Pharmacogenomics Approaches in Precision Medicine.

Precision medicine has greatly aided in improving health outcomes using earlier diagnosis and better prognosis for chronic diseases. It makes use of clinical data associated with the patient as well as their multi-omics/genomic data to reach a conclusion regarding how a physician should proceed with a specific treatment. Compared to the symptom-driven approach in medicine, precision medicine considers the critical fact that all patients do not react to the same treatment or medication in the same way. When considering the intersection of traditionally distinct arenas of medicine, that is, artificial intelligence, healthcare, clinical genomics, and pharmacogenomics-what ties them together is their impact on the development of precision medicine as a field and how they each contribute to patient-specific, rather than symptom-specific patient outcomes. This study discusses the impact and integration of these different fields in the scope of precision medicine and how they can be used in preventing and predicting acute or chronic diseases. Additionally, this study also discusses the advantages as well as the current challenges associated with artificial intelligence, healthcare, clinical genomics, and pharmacogenomics.

Compressional Optical Coherence Elastography of the Cornea.

Assessing the biomechanical properties of the cornea is crucial for detecting the onset and progression of eye diseases. In this work, we demonstrate the application of compression-based optical coherence elastography (OCE) to measure the biomechanical properties of the cornea under various conditions, including validation in an in situ rabbit model and a demonstration of feasibility for in vivo measurements. Our results show a stark increase in the stiffness of the corneas as IOP was increased. Moreover, UV-A/riboflavin corneal collagen crosslinking (CXL) also dramatically increased the stiffness of the corneas. The results were consistent across 4 different scenarios (whole CXL in situ, partial CXL in situ, whole CXL in vivo, and partial CXL in vivo), emphasizing the reliability of compression OCE to measure corneal biomechanical properties and its potential for clinical applications.

Heartbeat optical coherence elastography: corneal biomechanics in vivo.

SIGNIFICANCE: Mechanical assessment of the cornea can provide important structural and functional information regarding its health. Current clinically available tools are limited in their efficacy at measuring corneal mechanical properties. Elastography allows for the direct estimation of mechanical properties of tissues in vivo but is generally performed using external excitation force. AIM: To show that heartbeat optical coherence elastography (Hb-OCE) can be used to assess the mechanical properties of the cornea in vivo. APPROACH: Hb-OCE was utilized to detect Hb-induced deformations in the rabbit cornea in vivo without the need for external excitation. Furthermore, we demonstrate how this technique can distinguish corneal stiffness between untreated (UT) and crosslinked (CXL) tissue. RESULTS: Our results demonstrate that stiffness changes in the cornea can be detected using only the Hb-induced deformations in the cornea. Additionally, we demonstrate a statistically significant difference in strain between the UT and CXL corneas. CONCLUSIONS: Hb-OCE may be an effective tool for assessing the mechanical properties of the cornea in vivo without the need for external excitation. This tool may be effective for clinical assessment of corneal mechanical properties because it only requires optical coherence tomography imaging and data processing.

Heartbeat OCE: corneal biomechanical response to simulated heartbeat pulsation measured by optical coherence elastography.

SIGNIFICANCE: It is generally agreed that the corneal mechanical properties are strongly linked to many eye diseases and could be used to assess disease progression and response to therapies. Elastography is the most notable method of assessing corneal mechanical properties, but it generally requires some type of external excitation to induce a measurable displacement in the tissue. AIM: We present Heartbeat Optical Coherence Elastography (Hb-OCE), a truly passive method that can measure the elasticity of the cornea based on intrinsic corneal displacements induced by the heartbeat. APPROACH: Hb-OCE measurements were performed in untreated and UV-A/riboflavin cross-linked porcine corneas ex vivo, and a distinct difference in strain was detected. Furthermore, a partially cross-linked cornea was also assessed, and the treated and untreated areas were similarly distinguished. RESULTS: Our results suggest that Hb-OCE can spatially map displacements in the cornea induced by small fluctuations in intraocular pressure, similar to what is induced by the heartbeat. CONCLUSIONS: The described technique opens the possibility for completely passive and noncontact in vivo assessment of corneal stiffness.

Dynamic Optical Coherence Elastography of the Anterior Eye: Understanding the Biomechanics of the Limbus.

Purpose: Currently, the biomechanical properties of the corneo-scleral limbus when the eye-globe deforms are largely unknown. The purpose of this study is to evaluate changes in elasticity of the cornea, sclera, and limbus when subjected to different intraocular pressures (IOP) using wave-based optical coherence elastography (OCE). Special attention was given to the elasticity changes of the limbal region with respect to the elasticity variations in the neighboring corneal and scleral regions. Methods: Continuous harmonic elastic waves (800 Hz) were mechanically induced in the sclera near the corneo-sclera limbus of in situ porcine eye-globes (n = 8). Wave propagation was imaged using a phase-sensitive optical coherence tomography system (PhS-OCT). The eyes were subjected to five different IOP-levels (10, 15, 20, 30, and 40 mm Hg), and spatially distributed propagation velocities were calculated along corneal, limbal, and scleral regions. Finite element analysis (FEA) of the same regions under the same excitation conditions were conducted for further validation of results. Results: FEA demonstrated that the stiffness of the heterogeneous cornea-limbus-sclera transition can be characterized by phase velocity measurements of the elastic waves produced at 800 Hz in the anterior eye. Experimental results revealed that the wave speed in the limbus (cL = 6.5 m/s) is between the cornea (cc = 2.9 m/s) and sclera (cs = 10.0 m/s) at a physiological IOP level (15 mm Hg) and rapidly increases as the IOP level is increased, even surpassing the wave speed in the sclera. Finally, the change in elastic wave speed in the limbus (ΔcL∼18.5 m/s) was greater than in the cornea (Δcc ∼12.6 m/s) and sclera (Δcs∼8.1 m/s) for the same change in IOP. Conclusions: We demonstrated that wave-based OCE can be utilized to assess limbus biomechanical properties. Moreover, experimental evidence showed that the corneo-scleral limbus is highly nonlinear compared to the cornea and sclera when the eye-globe is deformed by an increase of IOP. This may suggest that the limbus has enough structural flexibility to stabilize anterior eye shape during IOP changes.

Multimodal quantitative optical elastography of the crystalline lens with optical coherence elastography and Brillouin microscopy.

Assessing the biomechanical properties of the crystalline lens can provide crucial information for diagnosing disease and guiding precision therapeutic interventions. Existing noninvasive methods have been limited to global measurements. Here, we demonstrate the quantitative assessment of the elasticity of crystalline lens with a multimodal optical elastography technique, which combines dynamic wave-based optical coherence elastography (OCE) and Brillouin microscopy to overcome the drawbacks of individual modalities. OCE can provide direct measurements of tissue elasticity rapidly and quantitatively, but it is a challenge to image transparent samples such as the lens because this technique relies on backscattered light. On the other hand, Brillouin microscopy can map the longitudinal modulus with micro-scale resolution in transparent samples. However, the relationship between Brillouin-deduced modulus and Young's modulus is not straightforward and sample dependent. By combining these two techniques, we can calibrate Brillouin measurements with OCE, based on the same sample, allowing us to completely map the Young's modulus of the crystalline lens. The combined system was first validated with tissue-mimicking gelatin phantoms of varying elasticities (N = 9). The OCE data was used to calibrate the Brillouin shift measurements and subsequently map the Young's modulus of the phantoms. After validation, OCE and Brillouin measurements were performed on ex-vivo porcine lenses (N = 6), and the Young's modulus of the lenses was spatially mapped. The results show a strong correlation between Young's moduli measured by OCE and longitudinal moduli measured by Brillouin microscopy. The correlation coefficient R was 0.98 for the phantoms and 0.94 for the lenses, respectively. The mean Young's modulus of the anterior and posterior lens was 1.98 ± 0.74 kPa and 2.93 ± 1.13 kPa, respectively, and the Young's modulus of the lens nucleus was 11.90 ± 2.94 kPa. The results presented in this manuscript open a new way for truly quantitative biomechanical mapping of optically transparent (or low scattering) tissues in 3D.

Optical coherence elastography of cold cataract in porcine lens.

Cataract is one of the most prevalent causes of blindness around the world. Understanding the mechanisms of cataract development and progression is important for clinical diagnosis and treatment. Cold cataract has proven to be a robust model for cataract formation that can be easily controlled in the laboratory. There is evidence that the biomechanical properties of the lens can be significantly changed by cataract. Therefore, early detection of cataract, as well as evaluation of therapies, could be guided by characterization of lenticular biomechanical properties. In this work, we utilized optical coherence elastography (OCE) to monitor the changes in biomechanical properties of ex vivo porcine lenses during formation of cold cataract. Elastic waves were induced in the porcine lenses by a focused micro air-pulse while the lenses were cooled, and the elastic wave velocity was translated to Young's modulus of the lens. The results show an increase in the stiffness of the lens due to formation of the cold cataract (from 11.3 ± 3.4 to 21.8 ± 7.8 kPa). These results show a relation between lens opacity and stiffness and demonstrate that OCE can assess lenticular biomechanical properties and may be useful for detecting and potentially characterizing cataracts.

Assessing colitis ex vivo using optical coherence elastography in a murine model.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes regions of ulceration within the interior of the colon. UC is estimated to afflict hundreds of thousands of people in the United States alone. In addition to traditional colonoscopy, ultrasonic techniques can detect colitis, but have limited spatial resolution, which frequently results in underdiagnoses. Nevertheless, clinical diagnosis of colitis is still generally performed via colonoscopy. Optical techniques such as confocal microscopy and optical coherence tomography (OCT) have been proposed to detect UC with higher resolution. However, UC can potentially alter tissue biomechanical properties, providing additional contrast for earlier and potentially more accurate detection. Although clinically available elastography techniques have been immensely useful, they do not have the resolution for imaging small tissues, such as in small mammalian disease models. However, OCT-based elastography, optical coherence elastography (OCE), is well-suited for imaging the biomechanical properties of small mammal colon tissue. METHODS: In this work, we induced elastic waves in ex vivo mouse colon tissue using a focused air-pulse. The elastic waves were detected using a phase-stabilized swept source OCE system, and the wave velocity was translated into stiffness. Measurements were taken at six positions for each sample to assess regional sample elasticity. Additional contrast between the control and diseased tissue was detected by analyzing the dispersion of the elastic wave and tissue optical properties obtained from the OCT structural image. RESULTS: The results show distinct differences (P<0.05) in the stiffness between control and colitis disease samples, with a Young's modulus of 11.8±8.0 and 5.1±1.5 kPa, respectively. The OCT signal standard deviations for control and diseased samples were 5.8±0.3 and 5.5±0.2 dB, respectively. The slope of the OCT signal spatial frequency decay in the control samples was 92.7±10.0 and 87.3±4.7 dB∙µm in the colitis samples. The slope of the linearly fitted dispersion curve in the control samples was 1.5 mm, and 0.8 mm in the colitis samples. CONCLUSIONS: Our results show that OCE can be utilized to distinguish tissue based on stiffness and optical properties. Our estimates of tissue stiffness suggest that the healthy colon tissue was stiffer than diseased tissue. Furthermore, structural analysis of the tissue indicates a distinct difference in tissue optical properties between the healthy and UC-like diseased tissue.