Excessive intake of animal fat and resultant obesity are major risk factors for prostate cancer. Because the composition of the gut microbiota is known to change with dietary composition and body ...type, we used prostate-specific
knockout mice as a prostate cancer model to investigate whether there is a gut microbiota-mediated connection between animal fat intake and prostate cancer. Oral administration of an antibiotic mixture (Abx) in prostate cancer-bearing mice fed a high-fat diet containing a large proportion of lard drastically altered the composition of the gut microbiota including
and
, inhibited prostate cancer cell proliferation, and reduced prostate
expression and circulating insulin-like growth factor-1 (IGF1) levels. In prostate cancer tissue, MAPK and PI3K activities, both downstream of the IGF1 receptor, were suppressed by Abx administration. IGF1 directly promoted the proliferation of prostate cancer cell lines DU145 and 22Rv1
. Abx administration also reduced fecal levels of short-chain fatty acids (SCFA) produced by intestinal bacteria. Supplementation with SCFAs promoted tumor growth by increasing IGF1 levels. In humans, IGF1 was found to be highly expressed in prostate cancer tissue from obese patients. In conclusion, IGF1 production stimulated by SCFAs from gut microbes influences the growth of prostate cancer via activating local prostate MAPK and PI3K signaling, indicating the existence of a gut microbiota-IGF1-prostate axis. Disrupting this axis by modulating the gut microbiota may aid in prostate cancer prevention and treatment. SIGNIFICANCE: These results suggest that intestinal bacteria, acting through short-chain fatty acids, regulate systemic and local prostate IGF1 in the host, which can promote proliferation of prostate cancer cells.
Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis ...neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.
Exaggerated thymic stromal lymphopoietin (TSLP) production and infiltration of basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development ...of food allergies. Although TSLP and basophils have been implicated in promotion of food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited basophils guide the progression of allergic inflammation in the skin to distant mucosal sites, such as the gastrointestinal tract, are poorly understood.
We sought to test the role of basophil-intrinsic IL-4 production in TH2 sensitization to food antigens in the skin and effector food-induced allergic responses in the gut.
Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intragastric antigen challenge to induce IgE-mediated food allergy. The requirement for basophil-derived IL-4 production for TH2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by using coculture experiments with naive T cells and in vivo by using Il4 3′UTR mice that selectively lack IL-4 production in basophils.
Epicutaneous food antigen sensitization is associated with infiltration of IL-4–competent innate immune cells to the skin, with basophils and eosinophils representing the predominant populations. In contrast to basophils, absence of eosinophils did not alter disease outcome. Coculture of IL-4–competent basophils together with dendritic cells and naive T cells was sufficient to promote TH2 polarization in an IL-4–dependent manner in vitro, whereas absence of basophil-intrinsic IL-4 production in vivo was associated with reduced food-induced allergic responses.
TSLP-elicited basophils promote epicutaneous sensitization to food antigens and subsequent IgE-mediated food allergy through IL-4. Strategies to target the TSLP–basophil–IL-4 axis in patients with AD might lead to innovative therapies that can prevent the progression of allergies to distant mucosal sites.
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Chlorogenic acids and caffeine are important for flavor formation as well as the health effect of green coffee brews and its extracts. The content of these compounds was determined by HPLC–DAD ...analysis in twelve samples of coffee from Robusta and Arabica types of different geographical origin including steamed and decaffeinated coffees. Generally, Robusta coffee extracts contain twice as much caffeine as Arabica, and its content varies from 3.41 % per dry mass in Arabica type from Laos or Rwanda to 8.16 % in Robusta coffee from Indonesia. The highest concentration of 5-
O
-caffeoylquinic acid (5-CQA) was obtained for both coffees from Uganda. Decaffeination process does not affect the concentration of this main chlorogenic acid, but steaming of the coffee beans with hot water produced a significant decrease in the level of 5-CQA. Antioxidant activity of coffee extracts was measured by CUPRAC and F–C assays, which really measure the reducing power of the sample components. Extracts of green coffee beans from Vietnam possessed the highest antioxidant activity in both assays.
Over the past several decades, the incidence of early-onset colorectal cancer (EOCRC; in patients <50 years old) has increased at an alarming rate. Although robust and scientifically rigorous ...epidemiological studies have sifted out environmental elements linked to EOCRC, our knowledge of the causes and mechanisms of this disease is far from complete. Here, we highlight potential risk factors and putative mechanisms that drive EOCRC and suggest likely areas for fruitful research. In addition, we identify inconsistencies in the evidence implicating a strong effect of increased adiposity and suggest that certain behaviours (such as diet and stress) might place nonobese and otherwise healthy people at risk of this disease. Key risk factors are reviewed, including the global westernization of diets (usually involving a high intake of red and processed meats, high-fructose corn syrup and unhealthy cooking methods), stress, antibiotics, synthetic food dyes, monosodium glutamate, titanium dioxide, and physical inactivity and/or sedentary behaviour. The gut microbiota is probably at the crossroads of these risk factors and EOCRC. The time course of the disease and the fact that relevant exposures probably occur in childhood raise important methodological issues that are also discussed.
Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been ...implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.
These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy.
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Purpose
This paper aims to present a comprehensive framework that integrates the emerging trends of servitization and digitalization in manufacturing. The influence between digitalization and ...servitization is defined and quantified. Their contribution to firm performance is analyzed.
Design/methodology/approach
This paper presents a theoretical model that captures the relationships between the analyzed variables. Drawing on the Spanish Business Strategy Survey, hypothesis testing is conducted using data on 828 Spanish industrial firms. Linear regression models are built to capture the effect of each variable on firm performance and the type of interaction between the variables.
Findings
Servitization and digitalization are positively related to firm performance. Digitalization positively mediates the relationship between servitization and firm performance. The mediating effect of digitalization contributes to differentiating between the direct and indirect effects of servitization on firm performance.
Practical implications
The paper provides a useful analysis framework for firms to evaluate servitization and digitalization as success strategies. It is proposed that firms must simultaneously commit to digital transformation and the incorporation of services to create value, especially in business-to-business settings. Servitization and digitalization interact to exert a greater influence on performance.
Originality/value
The paper contributes to the theory on service strategy by providing an analysis model that includes digitalization as a mediator of the relationship between servitization and firm performance. Digitalization may provide a mechanism to unlock the benefits of servitization and thereby enhance firm performance.
Antioxidant capacity of green coffee infusions (Arabica and Robusta of different geographical origin) has been studied e.g. with the use of Folin-Ciocalteu assay (the average: 1043 ± 577 mg GAE/L). ...The highest antioxidant capacity as well as concentration of three main 5-,4- and 3- caffeoylquinic acids were determined for Robusta coffee brews. According to assay used, steaming and decaffeination of Vietnam coffee beans altered the antioxidant capacity as well as the concentration of chlorogenic acids in the infusions. Additionally, the method of Cd, Cu, Mn, Pb and Se determination in green coffee beans and their infusions was optimized with the use of graphite furnace atomic absorption spectrometry. The average concentration of metals in green coffee beans was (mg/kg): Cd (0.013 ± 0.008), Cu (13.3 ± 2.8), Mn (24.1 ± 8.7), Pb (0.023 ± 0.005), Se (0.028 ± 0.010), respectively. The average leachabilities of Mn and Cu were established as 31.5% and 62.3%, respectively. The Cd, Pb and Se concentrations in the infusions were below the limits of detections.
•Green Robusta coffees possessed higher antioxidant capacity than Arabica.•Green Robusta brews contained more 4- & 3-caffeoylquinic acids than Arabica.•Cu, and Mn were detected in green coffee beans and brews.•No Cd, Pb, and Se could be detected in green coffee brews.
MiT family translocation renal cell carcinoma (MiT-RCC) harbors translocations involving the TFE3 or TFEB genes. RCC with TFEB amplification is also identified and is associated with a more ...aggressive clinical course. Accurate diagnosis of MiT-RCC is crucial for patient management. In this study, we evaluated the performance of the Archer FusionPlex assay for detection of MiT-RCC with TFE3 or TFEB translocations and TFEB amplifications. RNA was extracted from 49 RCC FFPE tissue samples with known TFE3/TFEB status (26 TFE3 FISH positive, 12 TFEB FISH positive, 4 TFEB amplified (1 case both split and amplified), and 8 FISH negative) using the Covaris extraction kit. Target enriched cDNA libraries were prepared using the Archer FusionPlex kit and sequenced on the Illumina NextSeq 550. We demonstrate that the age of the specimen, quality of RNA, and sequencing metrics are important for fusion detection. Fusions were identified in 20 of 21 cases less than 2 years old, and TFE3/TFEB rearrangements were detected in all cases with Fusion QC ≥ 100. The assay identified intrachromosomal inversions in two cases (TFE3-RBM10 and NONO-TFE3), usually difficult to identify by FISH assays. TFEB mRNA expression and the TFEB/TFE3 mRNA expression ratio were significantly higher in RCCs with TFEB fusion and TFEB gene amplification compared to tumors without TFEB fusion or amplification. A cutoff TFEB/TFE3 ratio of 0.5 resulted in 97.3% concordance to FISH results with no false negatives. Our study demonstrates that the FusionPlex assay successfully identifies TFE3 and TFEB fusions including intrachromosomal inversions. Age of the specimen and certain sequencing metrics are important for successful fusion detection. Furthermore, mRNA expression levels may be used for predicting cases harboring TFEB amplification, thereby streamlining testing. This assay enables accurate molecular detection of multiple subtypes of MiT-RCCs in a convenient workflow.
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