microRNAs are promising candidate breast cancer biomarkers due to their cancer-specific expression profiles. However, efforts to develop circulating breast cancer biomarkers are challenged by the ...heterogeneity of microRNAs in the blood. To overcome this challenge, we aimed to develop a molecular profile of microRNAs specifically secreted from breast cancer cells. Our first step towards this direction relates to capturing and analyzing the contents of exosomes, which are small secretory vesicles that selectively encapsulate microRNAs indicative of their cell of origin. To our knowledge, circulating exosome microRNAs have not been well-evaluated as biomarkers for breast cancer diagnosis or monitoring.
Exosomes were collected from the conditioned media of human breast cancer cell lines, mouse plasma of patient-derived orthotopic xenograft models (PDX), and human plasma samples. Exosomes were verified by electron microscopy, nanoparticle tracking analysis, and western blot. Cellular and exosome microRNAs from breast cancer cell lines were profiled by next-generation small RNA sequencing. Plasma exosome microRNA expression was analyzed by qRT-PCR analysis.
Small RNA sequencing and qRT-PCR analysis showed that several microRNAs are selectively encapsulated or highly enriched in breast cancer exosomes. Importantly, the selectively enriched exosome microRNA, human miR-1246, was detected at significantly higher levels in exosomes isolated from PDX mouse plasma, indicating that tumor exosome microRNAs are released into the circulation and can serve as plasma biomarkers for breast cancer. This observation was extended to human plasma samples where miR-1246 and miR-21 were detected at significantly higher levels in the plasma exosomes of 16 patients with breast cancer as compared to the plasma exosomes of healthy control subjects. Receiver operating characteristic curve analysis indicated that the combination of plasma exosome miR-1246 and miR-21 is a better indicator of breast cancer than their individual levels.
Our results demonstrate that certain microRNA species, such as miR-21 and miR-1246, are selectively enriched in human breast cancer exosomes and significantly elevated in the plasma of patients with breast cancer. These findings indicate a potential new strategy to selectively analyze plasma breast cancer microRNAs indicative of the presence of breast cancer.
Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of ...endometrial cancer cell lines in association with the G
/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane's potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.
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Tobacco smoking is the leading preventable cause of cancer. Moreover, continued smoking during cancer therapy reduces overall survival. Aware of the negative consequences of tobacco smoking and the ...challenges of smoking cessation, cancer patients are inquiring whether they should switch to electronic cigarettes (e-cigarettes). To obtain evidence-based data to inform this decision, we examined the effects of e-cigarette aerosol exposure on cisplatin resistance in head and neck cancer cells. Our results show that cancer cells exposed to e-cigarette aerosol extracts and treated with cisplatin have a significant decrease in cell death, increase in viability, and increase in clonogenic survival when compared to non-exposed cells. Moreover, exposure to e-cigarette aerosol extracts increased the concentration of cisplatin needed to induce a 50% reduction in cell growth (IC50) in a nicotine-independent manner. Tobacco smoke extracts induced similar increases in cisplatin resistance. Changes in the expression of drug influx and efflux transporters, rather than activation of cell growth-promoting pathways or DNA damage repair, contribute to e-cigarette induced cisplatin resistance. These results suggest that like combustible tobacco, e-cigarette use might increase chemotherapy resistance, and emphasize the urgent need for rigorous evaluation of e-cigarettes health effects to ensure evidence-based public health policies.
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Metal compounds abundant on Early Earth are thought to play an important role in the origins of life. Certain iron-sulfur minerals for example, are proposed to have served as primitive metalloenzyme ...cofactors due to their ability to catalyze organic synthesis processes and facilitate electron transfer reactions. An inherent difficulty with studying the catalytic potential of many metal compounds is the wide range of data and parameters to consider when searching for individual minerals and ligands of interest. Detecting mineral-ligand pairs that are structurally analogous enables more relevant selections of data to study, since structural affinity is a key indicator of comparable catalytic function. However, current structure-oriented approaches tend to be subjective and localized, and do not quantify observations or compare them with other potential targets. Here, we present a mathematical approach that compares structural similarities between various minerals and ligands using molecular similarity metrics. We use an iterative substructure search in the crystal lattice, paired with benchmark structural similarity methods. This structural comparison may be considered as a first stage in a more advanced analysis tool that will include a range of chemical and physical factors when computing mineral-ligand similarity. This approach will seek relationships between the mineral and enzyme worlds, with applications to the origins of life, ecology, catalysis, and astrobiology.
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In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors ...almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.
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Abstract One of the main objectives of the Mars Exploration Program is to search for evidence of past or current life on the planet. To achieve this, Mars exploration has been focusing on regions ...that may have liquid or frozen water. A set of critical areas may have seen cycles of ice thawing in the relatively recent past in response to periodic changes in the obliquity of Mars. In this work, we use convolutional neural networks to detect surface regions containing “brain terrain,” a landform on Mars whose similarity in morphology and scale to sorted stone circles on Earth suggests that it may have formed as a consequence of freeze/thaw cycles. We use large images (∼100–1000 megapixels) from the Mars Reconnaissance Orbiter to search for these landforms at resolutions close to a few tens of centimeters per pixel (∼25–50 cm). Over 58,000 images (∼28 TB) were searched (∼5% of the Martian surface), and we found detections in 201 images. To expedite the processing, we leverage a classifier network (prior to segmentation) in the Fourier domain that can take advantage of JPEG compression by leveraging blocks of coefficients from a discrete cosine transform in lieu of decoding the entire image at the full spatial resolution. The hybrid pipeline approach maintains ∼93% accuracy while cutting down on ∼95% of the total processing time compared to running the segmentation network at the full resolution on every image.
In the context of climate change with frequent natural disasters, disaster risk assessment can provide great help for related risk decision-making. Based on the theory of loss expectation, this paper ...presents a quantitative method to assess typhoon disaster risk. Among them, the probability of typhoon occurrence is calculated by fitting the optimal structure function of the sample to the joint distribution of wave height, water increment and wind speed. Then, the loss expectation is expressed as the product of typhoon occurrence probability and loss utility, which is used to quantify the loss result of a typhoon disaster. Using the loss utility theory, the risk grade chart is drawn with the direct economic loss rate and the proportion of the affected population as indicators. The results show that the absolute loss value considering the loss utility is slightly higher than the loss value of the quantitative algorithm by 2% to 25%, indicating that the new model reflects the social group’s aversion to typhoon disaster risk. As can be seen from the risk level zoning map, the highest combined risk level typhoons are Prapiroon 0606 and Chanthu 1003, with a risk level of Category 5. The typhoon comprehensive risk level before 2011 was ≥3, and the typhoon comprehensive risk level from 2012 to 2015 was ≤3. The evaluation model has certain feasibility and practicability, and the results can provide a basis and reference for typhoon risk assessment and decision-making.
Osteoarthritis (OA), the most common form of arthritis, is a significant public health burden in U.S. adults. Among its many risk factors, obesity is a key player, causing inflammation, pain, ...impaired joint function, and reduced quality of life. Dietary polyphenols and other bioactive compounds in berries, curcumin, and tea have shown effects in ameliorating pain and inflammation in OA, but few clinical studies have been reported. The purpose of the present study was to examine the effects of dietary strawberries on pain, markers of inflammation, and quality of life indicators in obese adults with OA of the knee. In a randomized, double-blind cross-over trial, adults with radiographic evidence of knee OA (
= 17; body mass index (BMI): (mean ± SD) 39.1 ± 1.5; age (years): 57 ± 7) were randomized to a reconstituted freeze-dried strawberry beverage (50 g/day) or control beverage daily, each for 12 weeks, separated by a 2-week washout phase (total duration, 26 weeks). Blood draws and assessments of pain and quality of life indicators were conducted using the Visual Analog Scale for Pain (VAS Pain), Measures of Intermittent and Constant Osteoarthritis Pain (ICOAP), and Health Assessment Questionnaire-Disability Index (HAQ-DI) questionnaires, which were completed at baseline and at weeks 12, 14, and 26 of the study. Among the serum biomarkers of inflammation and cartilage degradation, interleukin (IL)-6, IL-1β, and matrix metalloproteinase (MMP)-3 were significantly decreased after strawberry vs. control treatment (all
< 0.05). Strawberry supplementation also significantly reduced constant, intermittent, and total pain as evaluated by the ICOAP questionnaire as well as the HAQ-DI scores (all
< 0.05). No effects of treatment were noted on serum C-reactive protein (CRP), nitrite, glucose, and lipid profiles. Dietary strawberries may have significant analgesic and anti-inflammatory effects in obese adults with established knee OA.
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