Ensemble learning prediction framework for EGFR amplification status of glioma based on terahertz spectral features.

Epidermal growth factor receptor (EGFR) plays a pivotal role in the initiation and progression of gliomas. In particular, in glioblastoma, EGFR amplification emerges as a catalyst for invasion, proliferation, and resistance to radiotherapy and chemotherapy. Current approaches are not capable of providing rapid diagnostic results of molecular pathology. In this study, we propose a terahertz spectroscopic approach for predicting the EGFR amplification status of gliomas for the first time. A machine learning model was constructed using the terahertz response of the measured glioma tissues, including the absorption coefficient, refractive index, and dielectric loss tangent. The novelty of our model is the integration of three classical base classifiers, i.e., support vector machine, random forest, and extreme gradient boosting. The ensemble learning method combines the advantages of various base classifiers, this model has more generalization ability. The effectiveness of the proposed method was validated by applying an individual test set. The optimal performance of the integrated algorithm was verified with an area under the curve (AUC) maximum of 85.8 %. This signifies a significant stride toward more effective and rapid diagnostic tools for guiding postoperative therapy in gliomas.

Metal-Graphene Hybrid Terahertz Metasurfaces for Circulating Tumor DNA Detection Based on Dual Signal Amplification.

Terahertz (THz) spectroscopy has impressive capability for label-free biosensing, but its utility in clinical laboratories is rarely reported due to often unsatisfactory detection performances. Here, we fabricated metal-graphene hybrid THz metasurfaces (MSs) for the sensitive and enzyme-free detection of circulating tumor DNA (ctDNA) in pancreatic cancer plasma samples. The feasibility and mechanism of the enhanced effects of a graphene bridge across the MS and amplified by gold nanoparticles (AuNPs) were investigated experimentally and theoretically. The AuNPs serve to boost charge injection in the graphene film and result in producing a remarkable change in the graded transmissivity index to THz radiation of the MS resonators. Assay design utilizes this feature and a cascade hybridization chain reaction initiated on magnetic beads in the presence of target ctDNA to achieve dual signal amplification (chemical and optical). In addition to demonstrating subfemtomolar detection sensitivity and single-nucleotide mismatch selectivity, the proposed method showed remarkable capability to discriminate between pancreatic cancer patients and healthy individuals by recognizing and quantifying targeted ctDNAs. The introduction of graphene to the metasurface produces an improved sensitivity of 2 orders of magnitude for ctDNA detection. This is the first study to report the combined application of graphene and AuNPs in biosensing by THz spectroscopic resonators and provides a combined identification scheme to detect and discriminate different biological analytes, including nucleic acids, proteins, and various biomarkers.

Optimal frequency determination for terahertz technology-based detection of colitis-related cancer in mice.

Colorectal cancer is a prevalent malignancy globally, often linked to chronic colitis. Terahertz technology, with its noninvasive and fingerprint spectroscopic properties, holds promise in disease diagnosis. This study aimed to explore terahertz technology's application in colitis-associated cancer using a mouse model. Mouse colorectal tissues were transformed into paraffin-embedded blocks for histopathological analysis using HE staining. Terahertz transmission spectroscopy was performed on the tissue blocks. By comparing terahertz absorption differences, specific frequency bands were identified as optimal for distinguishing cancerous and normal tissues. The study revealed that terahertz spectroscopy effectively differentiates colitis-related cancers from normal tissues. Remarkably, 1.8 THz emerged as a potential optimal frequency for diagnosing colorectal cancer in mice. This suggests the potential for rapid histopathological diagnosis of colorectal cancer using terahertz technology.

Detection of biomarkers using terahertz metasurface sensors and machine learning.

To achieve classification and concentration detection of cancer biomarkers, we propose a method that combines terahertz (THz) spectroscopy, metasurface sensors, and machine learning. A metasurface sensor suitable for biomarker detection was designed and fabricated with five resonance frequencies in the range of 0.3-0.9 THz. We collected biomarkers of five types and nine concentrations at 100 sets of time-domain spectra per concentration. The spectrum is processed by noise reduction and fast Fourier transform to obtain the frequency-domain spectrum. Five machine learning algorithms are used to analyze time- and frequency-domain spectra and ascertain which algorithm is more suitable for the classification of the biomarker THz spectrum. Experimental results show that random forest can better distinguish five biomarkers with an accuracy of 0.984 for the time-domain spectrum. For the frequency-domain spectrum, the support vector machine performs better, with an accuracy of 0.989. For biomarkers at different concentrations, we used linear regression to fit the relationship between biomarker concentration and frequency shift. Experimental results show that machine learning can distinguish different biomarker species and their concentrations by the THz spectrum. This work provides an idea and data processing method for the application of THz technology in biomedical detection.

[Research Progress in the Application of Terahertz Spectroscopy and Imaging Technology in Stomatology].

Terahertz waves, the electromagnetic waves in the range of 0.1 to 10 THz, has the advantages of being damage-free, causing no ionizing radiation injury, and being capable of recognizing the fingerprint spectrum of molecular characteristics, thus holding encouraging prospects for wide applications in the field of biomedicine. Terahertz spectrum can be used to identify and characterize biological structures of different levels, from biomolecules such as proteins to cells and tissues, through the spectral signals and/or restored images of the samples. Herein, we summarized the current stomatogical application of and research progress in terahertz spectroscopy and imaging in dentistry, reported the latest research findings, strengths and limitations from three perspectives, tooth anatomical structure, the extent of caries progression, and oral soft tissue, and suggested possible directions for future exploration.

Quantitative analysis of aqueous biomolecular mixtures by THz spectroscopy based on high-power LiNbO3 radiation source.

The rapid and accurate identification of the types and contents of early pathological markers by THz technology are of particular importance for the prevention and treatment of major diseases. Nevertheless, these markers usually contain interference from water and other non-target molecules, resulting in low signal-to-noise ratio (SNR) and making identification and quantitative analysis difficult. Here, based on THz spectroscopy from a high-power THz source radiated by LiNbO3, we perform quantitative and real-time THz detection of mixtures (α-lactose monohydrate and 4-aminobenzoic acid) in liquids. The results demonstrate that the absorption spectra of the aqueous biomolecular mixtures exhibit an accumulation of THz features of each pure product, i.e., the amplitude of the absorption peaks is proportional to the mixing ratio, while the corresponding absorption baseline increases with decreasing concentration. Furthermore, the content of the target substance can be calculated from the linear relationship between the absorption spectra of pure and mixed samples. This technology will support the future application of THz-TDS in early disease diagnosis under complex states and environments.

Biomedical applications of terahertz spectra in clinical and molecular pathology of human glioma.

Gliomas are the most common type of primary tumor originating in the central nervous system of adults. Tumor histological type, pathological grade, and molecular pathology are significant prognosis and predictive factors. In this study, we were aiming to predict histological type and molecular pathological features based on terahertz time-domain spectroscopy technology. Nine gliomas with different grades, one meningioma, and one lymphoma were enrolled. There were significant differences in terahertz absorption coefficient between normal brain tissue, tumoral-periphery, and tumoral-center tissue in specific frequency bands (0.2-1.4 THz). Histological type, pathological grade, and glioma-specific biomarkers were closely related to the terahertz absorption coefficient in both tumoral-periphery and tumoral-center tissues. Interestingly, tumoral-periphery showed more obvious differences than tumoral-center tissues in almost all aspects. All the results show that the terahertz technology has potential application value in the intraoperative real-time glioma recognition and diagnosis of glioma histological and molecular pathological features.

Terahertz Spectroscopic Molecular Sensor for Rapid and Highly Specific Quantitative Analytical Gas Sensing.

Quantitative analytical gas sampling is of great importance in a range of environmental, safety, and scientific applications. In this article, we present the design, operation, and performance of a recently developed tabletop terahertz (THz) spectroscopic molecular sensor capable of rapid (minutes) and sensitive detection of polar gaseous analytes with near "absolute" specificity. A novel double-coil absorption cell design and an array of room-temperature sorbent-based preconcentration modules facilitate quantitative THz detection of light polar volatile compounds, which often challenge the capabilities of established gas sensing techniques. Acetone, ethanol, methanol, acetaldehyde, formaldehyde, and isoprene are detected at low parts-per-billion to high parts-per-trillion levels. This work evaluates performance-limiting factors for THz spectroscopy-based chemical identification: (1) spectral signal to noise and (2) preconcentrator efficiency.

Investigating the Impact of Synchrotron THz Radiation on the Corneal Hydration Using Synchrotron THz-Far Infrared Beamline.

Due to increasing interest in imaging, industrial, and the development of wireless communication operating at THz frequencies, it is crucial to ascertain possible health impacts arising from exposure to THz radiation. This paper reports on the pilot study of transmittance and absorbance spectra of the porcine cornea following THz frequency irradiation at a synchrotron THz/Far-IR beamline. The exposure period was 4 hours. One cornea was exposed to the radiation, with a second cornea acting as a control. An Attenuated Total Reflection (ATR) apparatus was used, and the frequency range of 2.4 to 8 THz was selected to evaluate any changes. It was found that the synchrotron THz radiation intensities are too low to produce induced corneal injury, but may lead to subtle changes in the state of water. Our results suggest that THz spectroscopy is a promising modality for corneal tissue hydration sensing.

Clinical and experimental study of a terahertz time-domain system for the determination of the pathological margins of laryngeal carcinoma.

OBJECTIVE: Laryngeal cancer is a common malignancy in otorhinolaryngological head and neck surgery, accounting for approximately one-third of all head and neck malignancies. Terahertz time-domain spectroscopy (THz-TDS) has recently been found to be useful for the detection of tumors. This study was conducted to investigate the application of THz-TDS in the diagnosis of pathological resection margins of laryngeal cancer. METHODS: Fresh laryngeal cancer tissues from 10 patients with laryngeal cancer were extracted, and after simultaneous HE staining and terahertz imaging, the tumor area, paracancerous area, and normal tissue area of each laryngeal cancer tissue sample were located under a microscope according to the pathological results of HE staining. RESULTS: The shape contours of the tumor region revealed by terahertz imaging maps and HE staining were similar. In the terahertz spectrum in the frequency range of 0.5-1.9 THz, both the absorption coefficient and refractive index values followed the order tumor > para cancer > normal tissue, with statistically significant differences (P < 0.01). When the terahertz frequency was 1.5 THz, the absorption coefficient of terahertz light waves by laryngeal cancer tissue and the percentage of nuclei showed an extremely high positive correlation (P < 0.01, r = 0.971). In the frequency ranges of 0.5-1.2 THz and 1.6-1.9 THz, the absorption coefficients of the highly differentiated group were higher than those of the moderately differentiated group. In the frequency range of 1.2-1.6 THz, the results were reversed, with statistically significant differences (P < 0.05). In the frequency range of 0.5-1.9 THz, the highly differentiated group had a higher refractive index than the moderately differentiated group, with a statistically significant difference (P < 0.05). CONCLUSIONS: THz-TDS can be used to determine the pathological margins of laryngeal cancer based on the absorption coefficient and refractive index, and the magnitudes of the absorption coefficient and refractive index are related to the percentage of nuclei. The degree of differentiation of laryngeal cancer tissue can be assessed by THz-TDS. The study shows that the terahertz time-domain system is promising for applications in the diagnosis of laryngeal cancer, especially for the more accurate identification of intraoperative margins.

Dental caries diagnosis using terahertz spectroscopy and birefringence.

Dental caries is a widespread chronic infectious disease which may induce a series of oral and general problems if untreated. As a result, early diagnosis and follow-up following radiation-free dental caries therapy are critical. Terahertz (THz) waves with highly penetrating and non-ionizing properties are ideally suited for dental caries diagnosis, however related research in this area is still in its infancy. Here, we successfully observe the existence of THz birefringence phenomenon in enamel and demonstrate the feasibility of utilizing THz spectroscopy and birefringence to realize caries diagnosis. By comparing THz responses between healthy teeth and caries, the transmitted THz signals in caries are evidently reduced. Concomitantly, the THz birefringence is also unambiguously inhibited when caries occurs due to the destruction of the internal hydroxyapatite crystal structure. This THz anisotropic activity is position-dependent, which can be qualitatively understood by optical microscopic imaging of dental structures. To increase the accuracy of THz technology in detecting dental caries and stimulate the development of THz caries instruments, the presence of significant THz birefringence effect induced anisotropy in enamel, in combination with the strong THz attenuation at the caries, may be used as a new tool for caries diagnosis.

Far-infrared terahertz properties of L-cysteine and its hydrochloride monohydrate.

As the building blocks of proteins, amino acids serve vital metabolic functions in addition to protein synthesis and thus attract enormous interest. Here we reported the far-infrared optical properties of L-cysteine (Lcys) and its hydrochloride monohydrate (LCHM) characterized by terahertz time-domain spectroscopy. The Lcys and LCHM exhibit quite distinct characteristics in the terahertz region due to diverse collective vibrations of the molecules, which is further confirmed by the solid-state density functional theory (DFT) calculations. The presented studies indicate that the intermolecular hydrogen bonds play a critical role in the far-infrared terahertz response of Lcys and LCHM.

Nanoantenna enhanced terahertz interaction of biomolecules.

Terahertz time-domain spectroscopy (THz-TDS) is a non-invasive, non-contact and label-free technique for biological and chemical sensing as THz-spectra are less energetic and lie in the characteristic vibration frequency regime of proteins and DNA molecules. However, THz-TDS is less sensitive for the detection of micro-organisms of size equal to or less than λ/100 (where, λ is the wavelength of the incident THz wave), and molecules in extremely low concentration solutions (like, a few femtomolar). After successful high-throughput fabrication of nanostructures, nanoantennas were found to be indispensable in enhancing the sensitivity of conventional THz-TDS. These nanostructures lead to strong THz field enhancement when in resonance with the absorption spectrum of absorptive molecules, causing significant changes in the magnitude of the transmission spectrum, therefore, enhancing the sensitivity and allowing the detection of molecules and biomaterials in extremely low concentration solutions. Herein, we review the recent developments in ultra-sensitive and selective nanogap biosensors. We have also provided an in-depth review of various high-throughput nanofabrication techniques. We also discussed the physics behind the field enhancements in the sub-skin depth as well as sub-nanometer sized nanogaps. We introduce finite-difference time-domain (FDTD) and molecular dynamics (MD) simulation tools to study THz biomolecular interactions. Finally, we provide a comprehensive account of nanoantenna enhanced sensing of viruses (like, H1N1) and biomolecules such as artificial sweeteners which are addictive and carcinogenic.

Rapid determination of aflatoxin B1 concentration in soybean oil using terahertz spectroscopy with chemometric methods.

Soybean oil is often contaminated by aflatoxin B1 (AFB1) which is regarded as a class I carcinogen. The feasibility of rapid determination of AFB1 in soybean oil with terahertz spectroscopy was examined. t-SNE, as the pre-treatment method was used to get the best features and combined with different chemometrics including least squares-support vector machines (LS-SVM), back propagation neural network (BPNN), random forest (RF) and partial least squares (PLS) to find the best determination model. The excellent prediction results could be obtained using BPNN combined with t-SNE with correlation the coefficient of prediction (Rp) was 0.9948 and the root-mean-square error of prediction (RMSEP) was 0.7124 µg/kg. Besides, THz spectroscopy was proved to be feasible to detect AFB1 at 1 µg/kg in soybean oil (over 90% accuracy). It was concluded that THz spectroscopy together with chemometrics would be a promising technique for rapid determination of the AFB1 concentration in soybean oil.

Utilizing multilayer structures to enhance terahertz characterization of thin films ranging from aqueous solutions to histology slides.

We propose a multilayer geometry to characterize thin-film samples in reflection terahertz time domain spectroscopy. Theory indicates that this geometry has higher sensitivity compared to ordinary transmission or reflection geometries when characterizing both low- and high-absorption samples. Pure water and water-ethanol mixtures are measured to verify the characterization accuracy of the proposed geometry and its capability to measure trace liquids. Paraffin-embedded oral cancer tissue is imaged to further show how the proposed geometry enhances the sensitivity for solid low-absorptive films.

Terahertz spectroscopy of gelatin-embedded human brain gliomas of different grades: a road toward intraoperative THz diagnosis.

We applied terahertz (THz)-pulsed spectroscopy to study ex vivo the refractive index and absorption coefficient of human brain gliomas featuring different grades, as well as perifocal regions containing both intact and edematous tissues. Glioma samples from 26 patients were considered and analyzed according to further histological examination. In order to fix tissues for the THz measurements, we applied gelatin embedding, which allows for sustaining their THz response unaltered, as compared to that of the freshly excised tissues. We observed a statistical difference between the THz optical constants of intact tissues and gliomas of grades I to IV, while the response of edema was similar to that of tumor. The results of this paper justify a potential of THz technology in the intraoperative label-free diagnosis of human brain gliomas for ensuring the gross-total resection.

Application of terahertz spectroscopy and chemometrics for discrimination of transgenic camellia oil.

Discrimination of transgenic edible oil has become the focus of attention in the field of food safety. In this paper, we propose a method for discrimination of transgenic edible oils by using terahertz spectroscopy combine with weighted linear discriminant analysis (WLDA). To evaluate the lustiness of the model, we employ successive projection arithmetic (SPA) and partial least squares (PLS) to verify the discrimination performance through variable selection. The results demonstrate that the SPA-WLDA model has higher classification accuracy than PLS-WLDA. In conclusion, terahertz spectroscopy is coupled with chemometrics is an effective method for discriminating various types of transgenic edible oils.

THz Spectroscopy for a Rapid and Label-Free Cell Viability Assay in a Microfluidic Chip Based on an Optical Clearing Agent.

Simple, rapid, and efficient cell viability assays play a fundamental role in much of biomedical research, including cell toxicology investigations and antitumor drug screening. Here, we demonstrate for the first time a rapid and label-free cell viability assay using THz spectroscopy in combination with a new optical clearing agent (OCA) and microfluidic technology. This strategy uses a considerably less absorptive OCA to replace the highly absorptive water molecules around the living cells and thus to decrease the background signal interference. Three low-viscosity oils were screened as potential OCA candidates, among which fluorinated oil was selected because of its lower absorption and lowest cytotoxicity. After the liquid medium was replaced with fluorinated oil in a microfluidic chip, an obvious THz spectral difference was observed between the fluorinated oils with and without living cells. This change in THz response was preliminarily attributed to the distinguishable signals between the cells and the fluorinated oil. In addition, we applied this method to cell viability assays of human breast cancer cells (MDA-MB-231) after treatment with different antitumor drugs. The results indicated that THz spectroscopy with the aid of the proposed water-replacement strategy presented excellent quantification of cell viability with the advantages of a rapid, label-free, nondestructive microassay, which offers significant potential to developing a convenient and practical cell analysis platform.

Inspecting human colon adenocarcinoma cell lines by using terahertz time-domain reflection spectroscopy.

Techniques to inspect and analyze human colorectal cancer cell lines by using terahertz time-domain attenuated total reflection spectroscopy (THz TD-ATR) were investigated. The characteristics of THz absorption spectra of two colorectal cancer cell lines DLD-1 and HT-29 in aqueous solutions with different concentrations were studied. Different spectral features were observed compared to normal cell line. Identification results based on different parameters including absorption coefficient, refractive index, real and imaginary parts of complex permittivity, dielectric loss tangent were discussed. This research may be promising for quick and instant inspection of liquid samples by using THz time-domain spectroscopy in medical applications.

Molecular Detection for Unconcentrated Gas With ppm Sensitivity Using 220-to-320-GHz Dual-Frequency-Comb Spectrometer in CMOS.

Millimeter-wave/terahertz rotational spectroscopy of polar gaseous molecules provides a powerful tool for complicated gas mixture analysis. In this paper, a 220-to-320-GHz dual-frequency-comb spectrometer in 65-nm bulk CMOS is presented, along with a systematic analysis on fundamental issues of rotational spectrometer, including the impacts of various noise mechanisms, gas cell, molecular properties, detection sensitivity, etc. Our comb spectrometer, based on a high-parallelism architecture, probes gas sample with 20 comb lines simultaneously. It does not only improve the scanning speed by 20, but also reduces the overall energy consumption to 90 mJ/point with 1 Hz bandwidth (or 0.5 s integration time). With its channelized 100-GHz scanning range and sub-kHz specificity, wide range of molecules can be detected. In the measurements, state-of-the-art total radiated power of 5.2 mW and single sideband noise figure of 14.6-19.5 dB are achieved, which further boost the scanning speed and sensitivity. Finally, spectroscopic measurements for carbonyl sulfide (OCS) and acetonitrile (CH CN) are presented. With a path length of 70 cm and 1 Hz bandwidth, the measured minimum detectable absorption coefficient reaches  cm. For OCS that enables a minimum detectable concentration of 11 ppm. The predicted sensitivity for some other molecules reaches ppm level (e.g., 3 ppm for hydrogen cyanide), or 10 ppt level if gas preconcentration with a typical gain of 10 is used.