Endurance training slows breast tumor growth in mice by suppressing Treg cells recruitment to tumors

BACKGROUND: Aerobic exercise has been shown to slow tumor progression in rodents and humans, but the mechanisms behind this effect are still unclear. Here we show that aerobic exercise in the form of chronic endurance training suppresses tumor recruitment of FoxP3+ Treg cells thus enhancing antitumor immune efficiency. METHODS: Adult wild-type and athymic BALB/c female mice were endurance-trained for 8 weeks. Circulating leukocytes as well as muscle and liver mtDNA copy number were compared to aged-matched concurrent sedentary controls to establish systemic effects. 4 T1 murine mammary tumor cells were injected subcutaneously to the 4th mammary pad at the end of the training period. Tumor growth and survival rates were compared, together with antitumor immune response. RESULTS: Exercised wild-type had 17% slower growth rate, 24% longer survival, and 2-fold tumor-CD+ 8/FoxP3+ ratio than sedentary controls. Exercised athymic BALB/c females showed no difference in tumor growth or survival rates when compared to sedentary controls. CONCLUSIONS: Cytotoxic T cells are a significant factor in endurance exercise-induced suppression of tumor growth. Endurance exercise enhances antitumor immune efficacy by increasing intratumoral CD8+/FoxP3+ ratio

Comparison of urinary scents of two related mouse species, Mus spicilegus and Mus domesticus.

International audienceWhereas the house mouse (Mus domesticus) has been studied extensively in terms of physiology/behavior and pheromonal attributes, the evolutionarily related mound-building mouse (Mus spicilegus) has received attention only recently due to its divergent behavioral traits related to olfaction. To date, no chemical studies on urinary volatile compounds have been performed on M. spicilegus. The rationale for our investigations was to determine if there are differences in urinary volatiles of intact and castrated M. spicilegus males and to explore further whether this species could utilize the same or structurally similar pheromones as the male house mouse, M. domesticus. The use of capillary gas chromatography/mass spectrometry (GC-MS) together with sorptive stir bar extraction sampling enabled quantitative comparisons between the intact and castrated M. spicilegus urinary profiles. Additionally, through GC-MS and atomic emission (sulfur-selective) detection, we identified qualitative molecular differences between intact M. spicilegus and M. domesticus. A series of volatile and odoriferous lactones and the presence of coumarin were the unique features of M. spicilegus, as was the notable absence of 2-sec-butyl-4,5-dihydrothiazole (a prominent M. domesticus male pheromone) and other sulfur-containing compounds. Castration of M. spicilegus males eliminated several substances, including delta-hexalactone and gamma-octalactone, and substantially decreased additional compounds, suggesting their possible role in chemical communication. Some other M. domesticus pheromone components were also found in M. spicilegus urine. These comparative chemical analyses support the notion of metabolic similarities as well as the uniqueness of some volatiles for M. spicilegus, which may have a distinct physiological function in reproduction and behavior

Cinacalcet suppresses calcification of the aorta and heart in uremic rats

High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels

Expansion of specialized epidermis induced by hormonal state and mechanical strain

In mammals, some sites of specialized skin such as the palms, soles, and lips grow proportionally with the animal. However, other types of specialized skin such as the nipple and anal/genital region are dramatically altered with changes of reproductive status. The specific cell types that mediate the growth of these sites have not been identified. In the mouse, we observed a dramatic expansion of the specialized epidermis of the nipple, coupled to changes in connective tissue and hair shaft density, which we designate as areola formation. During this process thymidine analog uptake was elevated in the epidermis and hair follicles. Although there were no changes in connective tissue cell proliferation, we did observe an altered expression of extracellular matrix genes. In addition, the fibroblasts of the virgin nipple areola and region showed increased transcript and protein levels for estrogen, progesterone, relaxin, and oxytocin relative to those of ventral skin. To determine the role of pregnancy, lactation hormonal milieu, and localized mechanical strain on areola formation, we created models that separated these stimuli and evaluated changes in gross structure, proliferation and protein expression. While modest increases of epidermal proliferation and remodeling of connective tissue occurred as a result of individual stimuli, areola formation required exposure to pregnancy hormones, as well as mechanical strain

Prophylaxis and Early Detection for Breast Cancer

Abstract: Breast cancer is steadily increasing in number in Japan due to less child bearing, less breast-feeding, and more westernization of life style than ever. Cancer registration in Osaka reported the incidence of breast cancer in 1996 to 1998 to be 41.1/100,000, four-times higher than the value in 1966-1968. Avoiding overweight, animal fat intake and mental stresses is a basic and easy measure for prevention of breast cancer. A unique study performed in Japan shows that daily intake of 10 or more cups of green tea inhibits development of breast cancer. A large-scale study by National Surgical Adjuvant Breast and Bowel Project (NSABP) revealed that 5-year tamoxifen administration to high-risk women decreased the incidence of breast cancer to 1/2 of the value for control women. Early diagnosis of breast cancer is most effectively achieved by fine needle aspiration cytology if the tumor is palpable with joint work with capable cytologists. More recently, stereo-tactic biopsy devices are available for non-palpable lesions. Mammography is more frequently used in mass screening system though its essential merit is yet to be investigated

Contrast-enhanced CT- and MRI-based perfusion assessment for pulmonary diseases: basics and clinical applications

Assessment of regional pulmonary perfusion as well as nodule and tumor perfusions in various pulmonary diseases are currently performed by means of nuclear medicine studies requiring radioactive macroaggregates, dual-energy computed tomography (CT), and dynamic first-pass contrast-enhanced perfusion CT techniques and unenhanced and dynamic first-pass contrast enhanced perfusion magnetic resonance imaging (MRI), as well as time-resolved three-dimensional or four-dimensional contrast-enhanced magnetic resonance angiography (MRA). Perfusion scintigraphy, single-photon emission tomography (SPECT) and SPECT fused with CT have been established as clinically available scintigraphic methods; however, they are limited by perfusion information with poor spatial resolution and other shortcomings. Although positron emission tomography with 15O water can measure absolute pulmonary perfusion, it requires a cyclotron for generation of a tracer with an extremely short half-life (2 min), and can only be performed for academic purposes. Therefore, clinicians are concentrating their efforts on the application of CT-based and MRI-based quantitative and qualitative perfusion assessment to various pulmonary diseases. This review article covers 1) the basics of dual-energy CT and dynamic first-pass contrast-enhanced perfusion CT techniques, 2) the basics of time-resolved contrast-enhanced MRA and dynamic first-pass contrast-enhanced perfusion MRI, and 3) clinical applications of contrast-enhanced CT- and MRI-based perfusion assessment for patients with pulmonary nodule, lung cancer, and pulmonary vascular diseases. We believe that these new techniques can be useful in routine clinical practice for not only thoracic oncology patients, but also patients with different pulmonary vascular diseases

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts

Cosmological and black hole brane-world Universes in higher derivative gravity

General model of multidimensional $R^2$-gravity including Riemann tensor square term (non-zero $c$ case) is considered. The number of brane-worlds in such model is constructed (mainly in five dimensions) and their properties are discussed. Thermodynamics of S-AdS BH (with boundary) is presented when perturbation on $c$ is used. The entropy, free energy and energy are calculated. For non-zero $c$ the entropy (energy) is not proportional to the area (mass). The equation of motion of brane in BH background is presented as FRW equation. Using dual CFT description it is shown that dual field theory is not conformal one when $c$ is not zero. In this case the holographic entropy does not coincide with BH entropy (they coincide for Einstein gravity or $c=0$ HD gravity where AdS/CFT description is well applied). Asymmetrically warped background (analog of charged AdS BH) where Lorentz invariance violation occurs is found. The cosmological 4d dS brane connecting two dS bulk spaces is formulated in terms of parameters of $R^2$-gravity. Within proposed dS/CFT correspondence the holographic conformal anomaly from five-dimensional higher derivative gravity in de Sitter background is evaluated.Comment: LaTeX file 40 pages, references added, version to appear in PR

Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms

In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable