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Leiomyosarcoma (LMS) has been challenging to diagnose because of limitations in clinical and radiographic predictors, as well as the lack of reliable serum or urinary biomarkers. Most uterine masses consist of benign leiomyoma (LM). However, it is currently a significant challenge in gynecology practice to differentiate LMS from LM. This inability poses grave consequences for patients, leading to a high number of unnecessary hysterectomies, infertility, and other major morbidities and possible mortalities. This study aimed to evaluate the use of Survivin-Sodium iodide symporter (Ad-Sur-NIS) as a reporter gene biomarker to differentiate malignant LMS from benign LM by using an F18-NaBF4 PET/CT scan. The PET/CT scan images showed a significantly increased radiotracer uptake and a decreased radiotracer decay attributable to the higher abundance of Ad-Sur-NIS in the LMS tumors compared to LM (p < 0.05). An excellent safety profile was observed, with no pathological or metabolic differences detected in Ad-Sur-NIS-treated animal versus the vehicle control. Ad-Sur-NIS as a PET scan reporter is a promising imaging biomarker that can differentiate uterine LMS from LM using F18-NaBF4 as a radiotracer. As a new diagnostic method, the F18 NaBF4 PET/CT scan can provide a much-needed tool in clinical practices to effectively triage women with suspicious uterine masses and avoid unnecessary invasive interventions.
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Genes Reporteros , Leiomioma , Leiomiosarcoma , Neoplasias Uterinas , Animales , Femenino , Humanos , Biomarcadores , Leiomioma/diagnóstico por imagen , Leiomiosarcoma/diagnóstico por imagen , Leiomiosarcoma/genética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Survivin , Neoplasias Uterinas/diagnóstico por imagen , Neoplasias Uterinas/genética , SimportadoresRESUMEN
The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc+/- mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc+/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc+/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.
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BACKGROUND: The popularity of short-term global health experiences amongst US medical students has been increasing. However, it remains a challenge for medical schools to comprehensively prepare students to work in an international environment and to contribute in ethically responsible and meaningful ways. Students of the Global Medicine program (GMED) of the UIC College of Medicine Center for Global Health set out to develop a pre-and-post travel curriculum that addresses some of these challenges. METHODS: The students surveyed the literature of 66 published global health curricula and identified aspects of pre-and-post travel training that were found to be under-addressed. They then developed a curriculum in conjunction with GMED faculty that incorporated these identified aspects of pre-and-post travel training. RESULTS: Five aspects of pre-and-post travel training were identified as being under-addressed in the literature while traveling. These domains include: [1] examining power relations associated with neo-colonization between and within countries; [2] training for bi-directional learning; [3] examining motivations and goals for participating in global health; [4] addressing personal resiliency and psychosocial wellbeing related to students' travel, and; [5] reflecting on the challenging aspects of the fieldwork experience. CONCLUSIONS: The student-driven curriculum is being integrated into the GMED program through structured didactic sessions, one-on-one mentor meetings and small group discussions. Once students have traveled, the curriculum will be evaluated with the foreign partners they visited.
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Educación Médica , Estudiantes de Medicina , Humanos , Curriculum , Aprendizaje , Mentores , Salud GlobalRESUMEN
In botanical extracts, highly abundant constituents can mask or dilute the effects of other, and often, more relevant biologically active compounds. To facilitate the rational chemical and biological assessment of these natural products with wide usage in human health, we introduced the DESIGNER approach of Depleting and Enriching Selective Ingredients to Generate Normalized Extract Resources. The present study applied this concept to clinical Red Clover Extract (RCE) and combined phytochemical and biological methodology to help rationalize the utility of RCE supplements for symptom management in postmenopausal women. Previous work has demonstrated that RCE reduces estrogen detoxification pathways in breast cancer cells (MCF-7) and, thus, may serve to negatively affect estrogen metabolism-induced chemical carcinogenesis. Clinical RCE contains ca. 30% of biochanin A and formononetin, which potentially mask activities of less abundant compounds. These two isoflavonoids are aryl hydrocarbon receptor (AhR) agonists that activate P450 1A1, responsible for estrogen detoxification, and P450 1B1, producing genotoxic estrogen metabolites in female breast cells. Clinical RCE also contains the potent phytoestrogen, genistein, that downregulates P450 1A1, thereby reducing estrogen detoxification. To identify less abundant bioactive constituents, countercurrent separation (CCS) of a clinical RCE yielded selective lipophilic to hydrophilic metabolites in six enriched DESIGNER fractions (DFs 01-06). Unlike solid-phase chromatography, CCS prevented any potential loss of minor constituents or residual complexity (RC) and enabled the polarity-based enrichment of certain constituents. Systematic analysis of estrogen detoxification pathways (ERα-degradation, AhR activation, CYP1A1/CYP1B1 induction and activity) of the DFs uncovered masked bioactivity of minor/less abundant constituents including irilone. These data will allow the optimization of RCE with respect to estrogen detoxification properties. The DFs revealed distinct biological activities between less abundant bioactives. The present results can inspire future carefully designed extracts with phytochemical profiles that are optimized to increase in estrogen detoxification pathways and, thereby, promote resilience in women with high-risk for breast cancer. The DESIGNER approach helps to establish links between complex chemical makeup, botanical safety and possible efficacy parameters, yields candidate DFs for (pre)clinical studies, and reveals the contribution of minor phytoconstituents to the overall safety and bioactivity of botanicals, such as resilience promoting activities relevant to women's health.
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Neoplasias de la Mama , Isoflavonas , Trifolium , Femenino , Humanos , Trifolium/química , Trifolium/metabolismo , Isoflavonas/farmacología , Isoflavonas/metabolismo , Estrógenos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
BACKGROUND: Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain. METHODS: NBL rats were treated with low-dose testosterone via slow-release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4-hydroxyestradiol (4OH-E2) and the nongenotoxic estrogen 2-fluoroestradiol (2F-E2) and in one experiment the aromatase inhibitor letrozole via custom-made slow-release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)-stained step sections were prepared and examined microscopically for proliferative lesions. RESULTS: Animals treated with 2F-E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F-E2 and 4OH-E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F-E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F-E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%. CONCLUSIONS: These findings indicate that long-term treatment with a nongenotoxic estrogen (2F-E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor-mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.
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Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Ratas , Animales , Andrógenos/metabolismo , Próstata/patología , Estradiol/metabolismo , Aromatasa/genética , Aromatasa/metabolismo , Letrozol/toxicidad , Letrozol/metabolismo , Estrógenos/farmacología , Neoplasias de la Próstata/patología , Testosterona/farmacología , Testosterona/metabolismo , Carcinogénesis/patología , Daño del ADNRESUMEN
Aggressive estrogen receptor (ER) positive breast cancer is frequently tamoxifen-resistant; alternative endocrine approaches exist for therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective progesterone receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. Unlike tamoxifen at human equivalent dose (HED) 101 mg/day, endoxifen at HED 24 mg/day significantly increased latency and reduced tumor growth relative to untreated controls. Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit tumor growth, while onapristone (HED 98 mg/day) had no tumor prevention efficacy in this model. Addition of UPA to endoxifen did not enhance preventive efficacy over endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation.
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Neoplasias de la Mama , Tamoxifeno , Femenino , Ratones , Humanos , Animales , Línea Celular Tumoral , Tamoxifeno/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular , Microambiente TumoralRESUMEN
Prostate cancer is a major male malignancy in many sub-Saharan countries in Africa. Because of resource limitations, screening, early detection, diagnosis, and curative treatments are not available for many men on the subcontinent, and there are even barriers to the treatment of advanced-stage metastatic prostate cancer. We are making the case for new approaches to the detection, diagnosis, and treatment of this malignancy in sub-Saharan Africa and other low-resource regions-approaches that differ from the ones available and used in high-income countries. The development of one-step dipstick-type detection assays of serum prostate-specific antigen (PSA) offers an approach to prostate cancer detection, treatment and monitoring that circumvents issues related to laboratory quality control and is also low-cost. Curative-intent treatments of early-stage prostate cancer are often unavailable in low-resource contexts, and most prostate cancers are not detected in Africa until they are at an advanced stage. Hence, androgen deprivation treatments, including orchiectomy and older low-cost drugs, offer feasible and affordable approaches to prolong survival and sustain a reasonable quality of life. However, clinical trials are needed to identify which of these androgen deprivation treatments are most efficacious and best tolerated to make progress in providing medical care for men with prostate cancer in sub-Saharan Africa and other low- and lower-middle-income areas around the world.
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Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/terapia , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Calidad de Vida , África del Sur del SaharaRESUMEN
Perinatal and neonatal exposure to bisphenol A (BPA) has been linked to enhancement of prostate carcinogenesis in rats induced by combined treatment with estradiol and testosterone, but human data are lacking. This study aimed to determine the effects of perinatal BPA exposure on induction of prostate cancer in rats by sequential treatment with N-methyl-N-nitrosamine (MNU) and continuous low dose administration of testosterone. Pregnant Sprague Dawley rats were exposed to BPA administered by subcutaneous Alzet minipumps at doses of 2.5 or 25 µg/kg body weight/day from gestational day 9 until postnatal day 28 when pups were weaned providing exposure of offspring in utero and via the mother's milk. At 10-12 weeks of age, one male offspring per litter was treated with an intraperitoneal injection of MNU after hormonal stimulation of prostatic cell proliferation followed two weeks later by subcutaneous insertion of Silastic implants containing testosterone until the termination of the study 57-58 weeks after MNU injection. The perinatal BPA exposure did not significantly affect the incidence of prostate carcinomas which was slightly lower in exposed rats (33-23 %) than in control animals (40 %). Carcinomas in all accessory sex glands combined were also insignificantly less frequent in exposed (46-48 %) than in control rats (60 %). The incidence of malignant tumors at any site in the body was significantly lower in exposed rats (81-65 %) than in controls (93 %). In conclusion, perinatal BPA exposure did not significantly modify prostate cancer induction by MNU plus testosterone in rats, unlike the enhancement of prostate carcinogenesis induced by treatments involving estradiol administration. Which of the two models of prostate carcinogenesis is more relevant for the human situation is unclear at present.
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Carcinoma , Neoplasias de la Próstata , Embarazo , Humanos , Ratas , Masculino , Animales , Recién Nacido , Testosterona , Ratas Sprague-Dawley , Metilnitrosourea/toxicidad , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/patología , Compuestos de Bencidrilo/toxicidad , Estradiol/toxicidad , CarcinogénesisRESUMEN
Selenomethionine (SeMet) did not prevent prostate cancer in the SELECT trial and in two hormone-driven rat models. However, we have shown that daily oral bolus administration of next-generation selenium forms, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) at 3 mg Se/kg body weight, inhibits prostate carcinogenesis in the TRAMP and pten-deficient mouse models and In Vivo growth of human prostate cancer cells. Here, we determined whether these Se forms prevent prostate cancer in a chemically induced-androgen promoted carcinogenesis rat model in which SeMet was not preventive. WU rats were treated with methylnitrosourea, and one week later, slow-release testosterone implants when they were randomized to groups fed AIN-93M diet supplemented with 3 ppm selenium as MSeA or MSeC or control diet. Mean survival, tumor incidence in all accessory sex glands combined (dorsolateral and anterior prostate plus seminal vesicle) and the incidence of tumors confined to dorsolateral and/or anterior prostate were not statistically significantly different among the groups. Thus, MSeA and MSeC feeding was not preventive in this model. The contrast with the inhibitory effects of MSeA and MSeC in mouse models may be due to differences in carcinogenic mechanisms, selenium dosage, delivery mode, and pharmacokinetics or fundamental rat-mouse differences in selenium metabolism.
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Neoplasias de la Próstata , Selenio , Andrógenos/metabolismo , Animales , Antioxidantes/metabolismo , Carcinogénesis/inducido químicamente , Carcinógenos , Dieta , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Compuestos de Organoselenio , Próstata/metabolismo , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/prevención & control , Ratas , Selenio/metabolismo , Selenio/farmacología , Selenocisteína/análogos & derivados , Selenocisteína/metabolismo , Selenocisteína/farmacología , Selenometionina/metabolismo , Selenometionina/farmacologíaRESUMEN
Animal models of prostate cancer are essential to identify chemopreventive treatments against this major male malignancy. The N-methyl-N-nitrosourea (MNU) plus testosterone rat model of prostate carcinogenesis is a reliable animal model that recapitulates human prostate cancer in many respects and has been used extensively in chemoprevention studies with good predictive value for the results of human clinical trials. The objective of this article is to describe the induction protocol of this model, demonstrate its robustness and reproducibility over time and across rat strains, provide diagnostic criteria for the identification of prostate lesions, and present the current tumor induction protocol so that others can use this model in a reliable manner. The majority of accessory sex gland tumors in this model are adenocarcinomas originating in the anterior and dorsolateral prostate that metastasize to lungs and abdominal structures. The rat strain used is of critical importance, with the commercially available Wistar WU and Fischer F344 strains yielding the highest tumor incidences. Low dose, long-term testosterone treatment is essential for a high tumor incidence, but in advanced stage, large adenocarcinomas do not appear to be androgen dependent. This rat model is a robust and reproducible prostate cancer animal model of human prostate cancer.
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Adenocarcinoma , Neoplasias de la Próstata , Adenocarcinoma/inducido químicamente , Animales , Carcinogénesis/inducido químicamente , Modelos Animales de Enfermedad , Humanos , Masculino , Próstata , Neoplasias de la Próstata/inducido químicamente , Ratas , Ratas Endogámicas F344 , Ratas Wistar , Reproducibilidad de los Resultados , TestosteronaRESUMEN
There is epidemiologic evidence to suggest that arsenic exposure is associated with risk of prostate cancer incidence and mortality. There are no studies indicating that arsenic can induce prostate cancer in animals. We evaluated whether drinking water exposure to sodium arsenite would affect prostate carcinogenesis in a rat model that depends on long-term low dose treatment with testosterone. WU rats received a sequential treatment with the antiandrogen flutamide followed by a single androgen administration to stimulate prostatic cell proliferation during which a single injection of N-methyl-N-nitrosourea was given. Two weeks later the animals received subcutaneous slow release testosterone-containing silastic tubing implants and provided with drinking water containing 5 mg/L sodium arsenite or with control drinking water for the duration of the 64 week-long experiment. Arsenite provided in drinking water did not modify the induction of prostate cancer in this rat model compared to control rats or survival. It also did not affect the growth of the animals or their drinking water intake. This animal study with drinking water exposure to 5 mg/L sodium arsenite does not support the notion that arsenic enhances prostate carcinogenesis.
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Arsénico , Arsenitos , Agua Potable , Neoplasias de la Próstata , Animales , Arsénico/toxicidad , Arsenitos/toxicidad , Carcinogénesis/inducido químicamente , Humanos , Masculino , Próstata , Neoplasias de la Próstata/inducido químicamente , Ratas , Compuestos de Sodio/toxicidad , TestosteronaRESUMEN
BACKGROUND: There is evidence to suggest that green tea soy may have protective effects against prostate cancer, but there are several epidemiologic and clinical studies that did not identify such an effect. We tested the notion of protective effects in a rat model of prostate carcinogenesis that has been predictive of the effects of selenium and vitamin E in randomized clinical trials and a human prostate cancer xenograft model in nude mice and rat prostate tumor cells transplanted in immune-competent syngeneic animals. METHODS: Prostate cancer was induced in rats with methylnitrosourea and testosterone and tumor incidence was determined. Subcutaneous tumor growth was measured resulting from injected cells isolated from rat prostate cancers grafted in syngeneic animals and from the prostate-specific antigen (PSA)-producing human prostate cancer PC346 xenografted in nude mice. Brewed decaffeinated green tea infusion or caffeinated green tea extract and the same 300 mg/ml concentration of caffeine were provided in drinking water of the rats and nude mice. RESULTS: Caffeinated green tea extract and caffeine provided in drinking water did not modify the induction of prostate cancer in the rat model compared with control rats. The same drinking water treatments also did not affect the growth and PSA production of PC346 human prostate cancer xenografts in nude mice and the growth of two transplantable rat prostate cancer tumor lines in Wistar Firth rats. Brewed green tea infusion as drinking water did also not affect tumor growth in these xeno- and allograft models. CONCLUSION: These animal studies with drinking water exposure to green tea and caffeine do not support the idea that green tea is protective against prostate cancer.
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Agua Potable , Neoplasias de la Próstata , Animales , Cafeína/uso terapéutico , Carcinogénesis , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , Extractos Vegetales/farmacología , Próstata/patología , Antígeno Prostático Específico , Neoplasias de la Próstata/patología , Ratas , Ratas Wistar , TéRESUMEN
DDX41 is a tumor suppressor frequently mutated in human myeloid neoplasms, but whether it affects hematopoiesis is unknown. Using a knockout mouse, we demonstrate that DDX41 is required for mouse hematopoietic stem and progenitor cell (HSPC) survival and differentiation, particularly of myeloid lineage cells. Transplantation of Ddx41 knockout fetal liver and adult bone marrow (BM) cells was unable to rescue mice from lethal irradiation, and knockout stem cells were also defective in colony formation assays. RNA-seq analysis of Lin-/cKit+/Sca1+Ddx41 knockout cells from fetal liver demonstrated that the expression of many genes associated with hematopoietic differentiation were altered. Furthermore, differential splicing of genes involved in key biological processes was observed. Our data reveal a critical role for DDX41 in HSPC differentiation and myeloid progenitor development, likely through regulating gene expression programs and splicing.
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Hematopoyesis , Células Madre Hematopoyéticas , Animales , Células de la Médula Ósea/metabolismo , Diferenciación Celular/genética , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Many studies have addressed the effects of dietary supplementation with soy protein on cancer risk and mortality, but there are only few randomized studies with soy in males. We used serum samples from a two-year trial of soy protein isolate supplementation in middle-aged to older males at risk of recurrence of prostate cancer after radical prostatectomy to determine soy effects on steroid hormones involved in prostate cancer (testosterone, SHBG, and estradiol) and explore the effects on biomarkers of the growth hormone/IGF-1 axis, apoptosis, and angiogenesis. Compared with a casein-based placebo, 18 mo, of consumption of 19.2 g/day of whole soy protein isolate containing 24 mg genistein-reduced circulating testosterone and SHBG, but not free testosterone, and did not affect serum concentrations of estradiol, VEGF, IGF-1, IGFBP-3, IGF-1/IGFBP-3 ratio, soluble Fas, Fas-ligand, and sFas/Fas-ligand ratio. Thus, soy protein supplementation for 18 mo, affected the androgen axis, but the effects on other cancer biomarkers remain to be more definitively determined. The study was registered at clinicaltrials.gov (NCT00765479).
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Factor I del Crecimiento Similar a la Insulina , Proteínas de Soja , Apoptosis , Biomarcadores de Tumor , Suplementos Dietéticos , Hormona del Crecimiento , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Prostatectomía , Proteínas de Soja/farmacología , TestosteronaRESUMEN
There is evidence to suggest that soy may be beneficial for prostate cancer patients, but few randomized trials have addressed this. We examined the effect of 6-8 mo soy protein supplementation on prostate specific antigen (PSA) serum levels in men who recurred (PSA > 0.1 ng/ml) within three years of prostatectomy. Sixteen men were randomized to 20 g soy protein (â¼24-26/day genistein; â¼40-43/day total isoflavones) or casein placebo. PSA was measured at base line and at 1, 2, 4, and 6-8 mo. Serum genistein levels greatly increased from baseline and cholesterol decreased in the soy group. In both treatment arms PSA increased similarly and PSA doubling times were not different over the 6-8 mo study duration. Two subjects in each group had stable PSA. A literature search for clinical studies of soy, isoflavones, and PSA revealed that supplementation with soy or isoflavones did not affect PSA in virtually all clinical studies identified. Although this study is too small to draw a definitive conclusion on the effect of soy protein on PSA in men with biochemical failure, the null finding in this study is consistent with the results of virtually all reports of soy and soy isoflavones in the literature.
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Isoflavonas , Neoplasias de la Próstata , Humanos , Isoflavonas/farmacología , Masculino , Proyectos Piloto , Antígeno Prostático Específico , Prostatectomía , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas de SojaRESUMEN
Pharmacological approaches to breast cancer risk-reduction for BRCA1 mutation carriers would provide an alternative to mastectomy. BRCA1-deficiency dysregulates progesterone signaling, promoting tumorigenesis. Selective progesterone receptor (PR) modulators (SPRMs) are therefore candidate prevention agents. However, their efficacy varies in different BRCA1-deficient mouse models. We examined chemopreventive efficacy of telapristone acetate (TPA), ulipristal acetate (UPA) and mifepristone (MFP) in mice with a conditional knockout of the Brca1 C-terminal domain. The SPRMs displayed a spectrum of efficacy: UPA was most effective, TPA less, and MFP ineffective. Compared to no-treatment controls, UPA reduced tumorigenesis (p = 0.04), and increased tumor latency (p = 0.03). In benign mammary glands, UPA decreased Ki67 (p < 0.001) and increased PR expression (p < 0.0001). RNA sequencing analysis revealed distinct gene expression in response to UPA and MFP. UPA downregulated glycolysis and extracellular matrix-inflammation genes (Fn1, Ptgs2, Tgfb2, Tgfb3) whereas MFP downregulated claudin genes and upregulated amino acid metabolism and inflammation genes. The anti-glucocorticoid effects of MFP appeared not to be tumor-protective, while altering estrogen receptor signaling and NF-kB activation. Our study points to an important role of epithelial PR and its paracrine action on the microenvironment in BRCA1-deficient mammary tumorigenesis, and prevention.
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Proteína BRCA1/genética , Neoplasias de la Mama/tratamiento farmacológico , Receptores de Progesterona/genética , Microambiente Tumoral/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/cirugía , Mastectomía , Ratones , Mifepristona/farmacología , Norpregnadienos/farmacología , Células del Estroma/metabolismo , Células del Estroma/patología , Microambiente Tumoral/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVES: Prostate cancer is the most commonly diagnosed cancer in Nigerian men despite the lack of PSA based screening. Current prevalence estimates in Nigeria are based on cancer registry data obtained primarily from hospital admissions and therefore not truly reflective of prostate cancer incidence. Prior autopsy series did not adhere to modern pathologic quality practices. The aim of this study was to explore the prevalence of asymptomatic prostate cancer among Nigerian men at the time of autopsy. METHODS: Prostates were collected at autopsy at the Universities of Lagos and Calabar Teaching Hospitals from men aged more than 40 who died from causes other than prostate cancer. Thirty-nine prostates from Nigerian men autopsied in 2017 to 2018 were formalin-fixed, weighed, and sliced at 4 mm intervals. Haematoxylin and eosin-stained paraffin sections were prepared from these slices. Presence and Gleason grade of prostatic adenocarcinomas and presence of high-grade prostatic intraepithelial neoplasia (HGPIN) were recorded. RESULTS: Mean age of cases was 55 ± 11 years and mean prostatic weight was 23.0 ± 10.9 g. The crude prevalence of HGPIN was 20.6%. Overall crude prevalence of prostate cancer was 8.8% (n = 34), increasing from 8.3% for men aged 40-59 (n = 23) to 10.0% for men ≥60 years old (n = 10). Two tumors were small and had Gleason Grade 3 + 3 or 3 + 4, and one large stage T3 tumor with Gleason Grade 4 + 3 disease and neuroendocrine appearance was found in a 54-year-old man. CONCLUSIONS: The 8.8% prevalence of subclinical prostate cancer at autopsy was similar to previously reported Nigerian studies with more limited tissue sampling (6.7%-10%), but considerably lower than estimates in other populations, including African Americans. Our findings suggest that latent, clinically asymptomatic prostate cancer is less frequent in Nigerians than in African Americans, despite shared genetic ancestry. Future studies with increased sample size are warranted to provide insight in the natural history and true prevalence of prostate cancer in West Africa.
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Adenocarcinoma , Autopsia/estadística & datos numéricos , Próstata/patología , Neoplasias de la Próstata , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Nigeria/epidemiología , Prevalencia , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Many studies have addressed effects of dietary supplementation with soy protein, but most have been inconsistent and few have been long-term studies in men. OBJECTIVES: This study was a secondary analysis of body weight, blood pressure, thyroid hormones, iron status, and clinical chemistry in a 2-y trial of soy protein supplementation in middle-aged to older men. METHODS: Data were analyzed as secondary outcomes of a randomized controlled trial of dietary supplementation with 20 g/d soy protein isolate, providing 41 mg/d total isoflavones and 23 mg/d genistein, in 44- to 75-y-old men who were at risk of cancer recurrence following prostatectomy randomized to soy (n = 50) or a casein-based placebo (n = 43). Weight, blood pressure, and blood samples were collected at baseline, every 2 mo in year 1, and every 3 mo in year 2. RESULTS: Compared with casein, soy supplementation did not affect body weight, blood pressure, serum total cholesterol, calcium, phosphorus, and thyroid hormones. Serum ferritin concentrations doubled over 2 y in both groups (117-129%), whereas hemoglobin and hematocrit increased slightly. In an exploratory subgroup analysis of soy group data, weight increased in subjects producing equol but not in nonproducers. Blood pressure was reduced in nonequol producers but not in producers. Other endpoints were not affected by equol production status. CONCLUSIONS: Soy protein supplementation for 2 y compared with a casein-based placebo did not affect body weight, blood pressure, serum total cholesterol, iron status parameters, calcium, phosphorus, and thyroid hormones. Exploratory analysis suggests that equol production status of subjects on soy may modify effects of soy on body weight and possibly blood pressure. This trial was registered at clinicaltrials.gov as NCT00765479.
Asunto(s)
Prostatectomía , Neoplasias de la Próstata/cirugía , Proteínas de Soja/administración & dosificación , Adulto , Anciano , Suplementos Dietéticos , Humanos , Masculino , Persona de Mediana Edad , Hormonas Tiroideas/sangre , Hormonas Tiroideas/metabolismoRESUMEN
PURPOSE: Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses. MATERIALS AND METHODS: Two sequential studies were performed in a total of 81 male NZW rabbits, 16-20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6, 7, 8, 8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on day 0. Animals were treated with timed release fentanyl patch (days 0-30), subcutaneous hydration (day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30 mg/kg once daily (days 3-30) and were followed for 30 days or to time of mortality. RESULTS: Study 1 revealed the estimated LD30, -50, -70, and -90 with 95% confidence intervals (CI) at 30 days to be 6.7 (CI: 5.9-7.4), 7.3 (CI: 6.7-7.8), 7.9 (CI: 7.3-8.4), and 8.8 (CI: 7.9-9.7) Gy, respectively. In study 2, a survey of blood coagulation and biochemical parameters were performed over time and necropsy. Complete blood counts taken from animals exposed to 7, 8, or 10 Gy, demonstrated dose-dependent depletion of lymphocytes, neutrophils, and platelets. Platelet counts recovered to baseline levels in survivors by day 30, whereas lymphocyte and neutrophil counts did not. Decedent animals demonstrated grade 3 or 4 neutropenia and lymphopenia at time of death; 64% of the decedents experienced a 30% or greater drop in hematocrit. Decedent animals demonstrated more than 100% increases from serum baseline levels of blood urea nitrogen, creatinine, aspartate aminotransferase, and triglyceride levels at the time of death whereas survivors on average demonstrated modest or no elevation. CONCLUSION: This NZW rabbit model demonstrates dose-dependent depletion of hematopoietic parameters. The LD50/30 of 7.8 Gy (95% CI: 6.6-8.4) with supportive care appears to be close to the ranges reported for rhesus macaques (5.25-7.44 Gy) and humans (6-8 Gy) with supportive care. These findings support the utility of the NZW rabbit model for further mechanistic investigation of acute radiation exposure and medical countermeasure testing.