Automated Detection and Scoring of Tumor-Infiltrating Lymphocytes in Breast Cancer Histopathology Slides.

Detection of tumor-infiltrating lymphocytes (TILs) in cancer images has gained significant importance as these lymphocytes can be used as a biomarker in cancer detection and treatment procedures. Our goal was to develop and apply a TILs detection tool that utilizes deep learning models, following two sequential steps. First, based on the guidelines from the International Immuno-Oncology Biomarker Working Group (IIOBWG) on Breast Cancer, we labeled 63 large pathology imaging slides and annotated the TILs in the stroma area to create the dataset required for model development. In the second step, various machine learning models were employed and trained to detect the stroma where U-Net deep learning structure was able to achieve 98% accuracy. After detecting the stroma area, a Mask R-CNN model was employed for the TILs detection task. The R-CNN model detected the TILs in various images and was used as the backbone analysis network for the GUI development of the TILs detection tool. This is the first study to combine two deep learning models for TILs detection at the cellular level in breast tumor histopathology slides. Our novel approach can be applied to scoring TILs in large cancer slides. Statistical analysis showed that the output of the implemented approach had 95% concordance with the scores assigned by the pathologists, with a p-value of 0.045 (n = 63). This demonstrated that the results from the developed software were statistically meaningful and highly accurate. The implemented approach in analyzing whole tumor histology slides and the newly developed TILs detection tool can be used for research purposes in biomedical and pathology applications and it can provide researchers and clinicians with the TIL score for various input images. Future research using additional breast cancer slides from various sources for further training and validation of the developed models is necessary for more inclusive, rigorous, and robust clinical applications.

Estimating Absorbed Dose to Breast Adipose Tissue from Mammograms.

PURPOSE: Breast cancer usually originates in the glandular tissue of the breast. However, inflamed adipose tissue surrounding glandular tissue may expedite the local growth of cancerous cells. Exposing adipose tissue to radiation during mammography might cause inflammation in adipose tissue. This inflammation depends on the dose, and thus on the energy deposited from the X-ray mammography. Therefore, estimating the absorbed dose to adipose tissue during mammography is essential in breast cancer research. MATERIALS AND METHODS: Absorbed dose to adipose tissue in the breast is determined using a new geometrical (semi-elliptical) model and Monte Carlo N-Particle transport code (MCNP6). X-ray mammogram images of patient breasts were taken as the basis of the new compressed breast geometry. The source probability density used in the MCNP6 code was generated from a published X-ray spectrum corresponding to tube voltage and air kerma. The relationship between various mammogram parameters such as peak tube voltage, compressed breast thickness, and adipose tissue weight fraction versus estimated absorbed dose is established for analysis. RESULTS: Significant influences of adipose tissue weight fraction on absorbed dose were observed. CONCLUSION: Estimating the absorbed dose to breast adipose tissue during mammography and patients' degree of obesity are important factors in breast cancer research.

Review of Biological Effects of Acute and Chronic Radiation Exposure on Caenorhabditis elegans.

Knowledge regarding complex radiation responses in biological systems can be enhanced using genetically amenable model organisms. In this manuscript, we reviewed the use of the nematode, Caenorhabditis elegans (C. elegans), as a model organism to investigate radiation's biological effects. Diverse types of experiments were conducted on C. elegans, using acute and chronic exposure to different ionizing radiation types, and to assess various biological responses. These responses differed based on the type and dose of radiation and the chemical substances in which the worms were grown or maintained. A few studies compared responses to various radiation types and doses as well as other environmental exposures. Therefore, this paper focused on the effect of irradiation on C. elegans, based on the intensity of the radiation dose and the length of exposure and ways to decrease the effects of ionizing radiation. Moreover, we discussed several studies showing that dietary components such as vitamin A, polyunsaturated fatty acids, and polyphenol-rich food source may promote the resistance of C. elegans to ionizing radiation and increase their life span after irradiation.

Breast cancer and the renin-angiotensin system (RAS): Therapeutic approaches and related metabolic diseases.

The Renin-Angiotensin System (RAS) is classically recognized for regulating blood pressure and fluid balance. Recently, this role has extended to other areas including inflammation, obesity, diabetes, as well as breast cancer. RAS components are expressed in normal and cancerous breast tissues, and downregulation of RAS inhibits metastasis, proliferation, angiogenesis, and desmoplasia in the tumor microenvironment. Therefore, RAS inhibitors (Angiotensin receptor blockers, ARBs, or angiotensin converting enzyme inhibitors, ACE-I) may be beneficial as preventive adjuvant therapies to thwart breast cancer development and improve outcomes, respectively. Given the beneficial effects of RAS inhibitors in metabolic diseases, which often co-exist in breast cancer patients, combining RAS inhibitors with other breast cancer therapies may enhance the effectiveness of current treatments. This review scrutinizes above associations, to advance our understanding of the role of RAS in breast cancer and its potential for repurposing of RAS inhibitors to improve the therapeutic approach for breast cancer patients.

A General New Method for Calculating the Molecular Nonpolar Surface for Analysis of LC-MS Data.

The accurate determination of the nonpolar surface area of glycans is vital when utilizing liquid chromatograph/mass spectrometry (LC-MS) for structural characterization. A new approach for defining and computing nonpolar surface areas based on continuum solvation models (CS-NPSA) is presented. It is based on the classification of individual surface elements representing the solvent accessible surface used for the description of the polarized charge density elements in the CS models. Each element can be classified as polar or nonpolar according to a threshold value. The summation of the nonpolar elements then results in the NPSA resulting in a very fine resolution of this surface. The further advantage of the CS-NPSA approach is the straightforward connection to standard quantum chemical methods and program packages. The method has been analyzed in terms of the contributions of different atoms to the NPSA. The analysis showed that not only atoms normally classified as nonpolar contributed to the NPSA, but at least partially also atoms next to polar atoms or N atoms. By virtue of the construction of the solvent accessible surface, atoms in the inner regions of a molecule can be automatically identified as not contributing to the NPSA. The method has been applied to a variety of examples such as the phenylbutanehydrazide series, model dextrans consisting of glucose units and biantennary glycans. Linear correlation of the CS-NPSA values with retention times obtained from liquid chromatographic separations measurements in the mentioned cases give excellent results and promise for more extended applications on a larger variety of compounds.

Dynamics of intracellular stress-induced tRNA trafficking.

Stress is known to induce retrograde tRNA translocation from the cytoplasm to the nucleus but translocation kinetics and tRNA-spatial distribution have not been characterized previously. We microinject fluorescently-labeled tRNA into living cells and use confocal microscopy to image tRNA spatial distribution in single cells at various levels of starvation and to determine translocation rate constants. Retrograde tRNA translocation occurs reversibly, within minutes after nutrition depletion of the extracellular medium. Such nutritional starvation leads to down-regulation of tRNA nuclear import and nearly complete curtailment of its nuclear export. Nuclear tRNA accumulation is suppressed in cells treated with the translation inhibitor puromycin, but is enhanced in cells treated with the microtubule inhibitor nocodazole. tRNA in the cytoplasm exhibits distinct spatial distribution inconsistent with diffusion, implying that such distribution is actively maintained. We propose that tRNA biological complexes and/or cytoplasmic electric fields are the likely regulators of cytoplasmic tRNA spatial distribution.

Microdroplet-based On-Demand Drawing of High Aspect-Ratio Elastomeric Micropillar and Its Contact Sensing Application.

High aspect-ratio elastomeric micropillars play important roles as the platform for microscale sensing and actuation. Many soft-lithographic techniques have been developed for their facile realization but most of the techniques are limited to build the micropillars only on totally flat, widely accessible substrate areas with the micropillar's structural characteristics completely predetermined, leaving little room for in situ control. Here we demonstrate a new technique which overcomes these limitations by directly drawing micropillars from pipette-dispensed PDMS microdroplets using vacuum-chucked microspheres. The combined utilization of PDMS microdroplets and microspheres not only enables the realization of microsphere-tipped PDMS micropillars on non-flat, highly space-constrained substrate areas at in situ controllable heights but also allows arraying of micropillars with dissimilar heights at a close proximity. To validate the new technique's utility and versatility, we realize PDMS micropillars on various unconventional substrate areas in various configurations. We also convert one of them, the optical fiber/micropillar hybrid, into a soft optical contact sensor. Both the fabrication technique and the resulting sensing scheme will be useful for future biomedical microsystems.

Nanoscale patterning of biopolymers for functional biosurfaces and controlled drug release.

We compare the rates of drug release from nanopatterned and flat biodegradable polymer surfaces, and observe significantly lower release rates from the nanopatterned surfaces. Specifically, we nanopattern poly(l-lactic acid) (PLLA), a biodegradable polymer frequently used for fabricating drug-eluting coronary stents, through microtransfer molding and solvent casting and investigate the nanopattern's impact on the release of sirolimus, an immunosuppressant agent, coated on the PLLA surface using high performance liquid chromatography/mass spectrometry. We find that PLLA surfaces nanopatterned with 750 nm-pitch nanocup or nanocone arrays exhibit drug release rates significantly lower (25-30%) than that of the flat surface, which is counter-intuitive given the nanopattern-induced increase in their surface areas. Based on diffusion and meniscus curvature minimization analyses, we attribute the decreased drug release rate to the incomplete wetting of the nanopatterned surface. These results provide new insights on how the surface nanopatterning of biomaterials can functionalize the surface and tailor the release kinetics of therapeutic agents coated on it for controlled drug elution.

Elastomer-based opto-thermo-mechanical actuation for autonomous, self-powered light level control.

We present an autonomous, self-powered solar light controller based on functional integration of a flexible cantilever light guide and a paraffin wax-based optothermal actuator. The controller utilizes the optothermally induced volume increase in the elastomer-encapsulated paraffin wax to produce pneumatic force, which subsequently actuates the cantilever light guide to control the level of frustrated total internal reflection. In its linear response regime, it demonstrated 33% reduction in light intensity fluctuation in terms of the root-mean-square value.

Bio-inspired thin and flat solar concentrator for efficient, wide acceptance angle light collection.

We present a novel thin and flat solar concentrator design, inspired by the structure and optical functionality of the ommatidium in the compound eye of insects. By combining a microlens with a curved light guide, rather than the conventionally employed dielectric or metallic reflectors, we could simultaneously achieve low-loss light redirection and wide acceptance angle without compromising the overall thinness or flatness of the concentrator. Through design optimizations, we could achieve optical concentration factors up to 39 and acceptance angle up to ±15° while maintaining the thickness of the concentrator under 1.1 cm for a length of 20 cm. We also showed that the optical concentration factor can be further increased to 81 through tapering of the geometry.