Quantitative Study of Nano to Submicron Scales Intracellular Structural Disorder Using Electron and Confocal Microscopies: Application to Cancer Detection

Cancer is one of the leading causes of death with over a million people being diagnosed every year. Many cancers eventually result in death because they go undetected in their early stages when they can be cured. The conventional techniques used for cancer diagnostics exhibit limitations in detecting early stage cancer, which has nano-scale structural changes. On the other hand, alcoholism is one of the biggest cause of health problems. This study examines the effect of alcohol in early stage carcinogenesis in the colon and healthy hippocampal cells of mice models by quantifying the structural changes in their nuclei via transmission electron microscopy (TEM). The technique utilizes the Mesoscopic Physics based concept of analyzing cellular structure by looking their light localization properties. In a seperate study, we also examined the correlation between MUC13 mucin and the tumorigenicity level in pancreatic cells via confocal microscopy imaging. The TEM and confocal images are used to construct and optical lattice system whose nano- to sub-micron scale mass density fluctuations are subsequently evaluated by statistically analyzing the spatially localized eigenfucntions of these optical lattice systems via inverse participation ratio (IPR) method. The results of TEM studies show that while the alcohol doesnot introduce carcinogenesis in healthy colon cells, it aggrandizes a pre-existing carcinogenesis. In hippocampal cells, alcoholism causes nanoscale morphological alterations in nuclei. The confocal studies of pancreatic cells show an existance of semblant correlation between MUC13 mucin expression and the stage of pancreatic cancer

Infrared Spectroscopy of Serum Samples for Disease Diagnostics

The fundamental vibrational modes of biological constituents in the tissues and the complex body fluids coincide with optical frequencies in the infrared region. Therefore, spatially resolved molecular compositions and interaction information within the biological materials can be extracted non-destructively using IR radiation without the use of labels or probes. However, the feasibility of this technique to elucidate constituent molecular compositions and interactions within the diagnostic mediums is not well explored. This study demonstrates an application of infrared (IR) spectroscopy of sera for monitoring inflammatory bowel diseases (IBD) and various cancers. Using samples from experimental mice and human patients, the power of IR spectroscopy in structural studies of proteins and other complex band contours are explored to find spectral signatures. Two experimental models of IBD; interleukin 10 knockouts (IL10-/-) and Dextran Sodium Sulfate (DSS) induced mouse shows diagnostic accuracy with 80-100% sensitivity and specificity values. Importantly, the findings of human IBD patients’ serum also show promising results resembling our proofs-of-concept investigations of mouse models. Maximum values of sensitivity and specificity are 100% and 86%, respectively, in human samples. Similarly, in cancer studies, the EL4 mouse model of non-Hodgkin lymphoma (NHL) and a B16 mouse model of the subcutaneous melanoma are used to extract a snapshot of tumor-associated alteration in the serum. The study of both cancer-bearing mouse models in wild types (WT) and their corresponding control types emphasizes the diagnostic potential of this approach as a screening technique for the NHL and melanoma skin cancer. The breast cancer (BC) -associated protein conformational alteration in the serum samples shows the sensitivity and the specificity of identifying spectral signatures were both 90%. All in all, IR spectroscopy of serum samples accompanied by spectral analysis technique shows some promising results for disease diagnostics. The brief outlook of the fundamentals of the infrared detection technique and their applicability for the development of portable spectroscopy is also provided

Feasibility of a Novel Sparse Orthogonal Collimator–Based Preclinical Total Marrow Irradiation for Enhanced Dosimetric Conformality

Total marrow irradiation (TMI) has significantly improved radiation conditioning for hematopoietic cell transplantation in hematologic diseases by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. Recently, preclinical three-dimensional image–guided TMI has been developed to enhance mechanistic understanding of the role of TMI and to support the development of experimental therapeutics. However, a dosimetric comparison between preclinical and clinical TMI reveals that the preclinical TMI treatment lacks the ability to reduce the dose to some of the vital organs that are very close to the skeletal system and thus limits the ability to evaluate radiobiological relevance. To overcome this limit, we introduce a novel Sparse Orthogonal Collimator (SOC)–based TMI and evaluate its ability to enhance dosimetric conformality. The SOC-TMI–based dose modulation technique significantly improves TMI treatment planning by reducing radiation exposures to critical organs that are close to the skeletal system that leads to reducing the gap between clinical and preclinical TMI

TEM study of chronic alcoholism effects on early carcinogenesis by probing the nanoscale structural alterations of cell nuclei

Nanoscale structural alteration in the nuclei of cells with the progression of carcinogenesis is due to the rearrangements of the basic building blocks in the cell such as DNA, RNA, lipids, etc. Although epigenetic modifications underlie the development of cancer, exposure to carcinogenic chemicals such as alcohol also enhances the development of cancer. We report the effects of chronic alcoholism on early-carcinogenesis based on changes in the degree of nanoscale structural alterations (Ld) in nuclei. For this, transmission electron microscopy (TEM) imaging of the nuclei of colonic cells is performed for the following four mouse models: control mice; chronic alcoholic mice treated with ethanol (i.e., EtOH mice); mice treated with colonic carcinogen azoxymethane (AOM) and dextran sulfate sodium (DSS) that induced colitis (i.e., AOM + DSS mice); and chronic alcoholic or EtOH treated mice, together with AOM and DSS treatment (i.e., AOM + DSS + EtOH mice). The disordered optical lattices are constructed from their respective TEM images of thin colonic cell nuclei and the Ld values are calculated using the inverse participation ratio (IPR) technique from the spatially localized eigenfunctions of these lattices. Results show no significant difference in the average Ld value of the colon cell nuclei of alcohol treated mice relative to its control [i.e., Ld(C) ∼ Ld(EtOH)]; however, an increase in the Ld value of alcohol treated precancerous cells [i.e., Ld(AOM + DSS + EtOH) \u3e Ld(AOM + DSS)], indicating that alcohol accelerates the early carcinogenic process

Light localization properties of weakly disordered optical media using confocal microscopy: Application to cancer detection

We have developed a novel technique to quantify submicron scale mass density fluctuations in weakly disordered heterogeneous optical media using confocal fluorescence microscopy. Our method is based on the numerical evaluation of the light localization properties of an \u27optical lattice\u27 constructed from the pixel intensity distributions of images obtained with confocal fluorescence microscopy. Here we demonstrate that the technique reveals differences in the mass density fluctuations of the fluorescently labeled molecules between normal and cancer cells, and that it has the potential to quantify the degree of malignancy of cancer cells. Potential applications of the technique to other disease situations or characterizing disordered samples are also discussed

Recent Progress on Extended Wavelength and Split-Off Band Heterostructure Infrared Detectors

The use of multilayer semiconductor heterojunction structures has shown promise in infrared detector applications. Several heterostructures with innovative compositional and architectural designs have been displayed on emerging infrared technologies. In this review, we aim to illustrate the principles of heterostructure detectors for infrared detection and explore the recent progress on the development of detectors with the split-off band and threshold wavelength extension mechanism. This review article includes an understanding of the compositional and the architectural design of split-off band detectors and to prepare a database of their performances for the wavelength extension mechanism. Preparing a unique database of the compositional or architectural design of structures, their performance, and penetrating the basics of infrared detection mechanisms can lead to significant improvements in the quality of research. The brief outlook of the fundamentals of the infrared detection technique with its appropriateness and limitations for better performance is also provided. The results of the long-term study presented in this review article would be of considerable assistance to those who are focused on the heterostructure infrared detector development

Quantification of photonic localization properties of targeted nuclear mass density variations: Application in cancer-stage detection

Light localization is a phenomenon which arises due to the interference effects of light waves inside a disordered optical medium. Quantification of degree light localization in optical media is widely used for characterizing degree of structural disorder in that media. Recently, this light localization approach was extended to analyze structural changes in biological cell like heterogeneous optical media, with potential application in cancer diagnostics. Confocal fluorescence microscopy was used to construct “optical lattices,” which represents 2-dimensional refractive index map corresponding to the spatial mass density distribution of a selected molecule inside the cell. The structural disorder properties of the selected molecules were evaluated numerically using light localization strength in these optical lattices, in a single parameter called “disorder strength.” The method showed a promising potential in differentiating cancerous and non-cancerous cells. In this paper, we show that by quantifying submicron scale disorder strength in the nuclear DNA mass density distribution, a wide range of control and cancerous breast and prostate cells at different hierarchy levels of tumorigenicity were correctly distinguished. We also discuss how this photonic technique can be used in examining tumorigenicity level in unknown prostate cancer cells, and potential to generalize the method to other cancer cells