Hormone Rhythms and Breast Cancer Chronoepidemiology: Salivary Progesterone Concentrations in Pre- and Post-Menarchal Girls and in Normal Premenopausal Women

Orcadian and circatrigintan time series of salivary progesterone levels in premenarchal and adolescent girls and healthy mature premenopausal women have been investigated as a possible determinant for breast cancer risk. Circadian variations in progesterone appear to be more random than systematic and estimates of total daily progesterone output are better represented by samples pooled from several 2-hr specimens. Different patterns of circatrigintan progesterone secretion in girls are recognised and relate to those experienced in infertile and fertile women, though their relation to chronological or menarchal age is as yet uncertain. These data suggest that the measurement of salivary progesterone at premenarche, adolescence and maturity is a feasible, though statistically difficult, study for prospective identification of individuals at risk for breast cancer.     

Early changes in mitochondrial monoamine oxidase activity of rat liver during 2-acetylaminofluorene feeding

The activities of mitochondrial type A and B monoamine oxidase were determined in the liver of rats fed a diet containing 2-acetylaminofluorene (AAF). Three days after the initiation of AAF-feeding, there was a significant decrease of type B monoamine oxidase activity without affect on type A enzyme. The decreased activity of type B monoamine oxidase, which reached a minimum after three weeks, was sustained for as long as AAF-feeding was continued. Sex-related difference in response to AAF was seen in the rat with respect to the onset and the intensity of the decreased type B monoamine oxidase activity, male rats being more sensitive to the carcinogen than female rats. In contrast to the in vivo effect, AAF showed a potent inhibitory effect on type A monoamine oxidase, rather than on type B enzyme, when added in vitro. The pI₅₀ values were estimated to be 7.5 against type A monoamine oxidase and 4.1 against type B enzyme, respectively. The in vitro inhibition of both types of monoamine oxidase by AAF was competitive. The K_i values for AAF were calculated to be 9.51 · 10^?9 M for type A monoamine oxidase and 1.30 · 10^?5 M for type B enzyme, respectively. In accordance with the potent inhibitory effect of AAF on type A monoamine oxidase in vitro, a single administration of the carcinogen, at a dose of 50 mg/kg, resulted in a marked and temporal decrease of the enzyme activity in the mitochondria of male rat liver. Recovery of the decreased type B monoamine oxidase activity was slow, and the enzyme activity did not return to control levels, even if rats were fed the basal diet for 2 or 4 weeks after the cessation of AAF-feeding.     

Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite–Protein Physical Interaction Subnetworks Altered in Cancer

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.     

Feeding preference by the male blowfly Phormia regina for some natural foods and its relation to carbohydrate, amino acid, and alcohol content

The male blowfly, Phormia regina Meigen shows preference among a variety of natural and artificial foods. In a laboratory study preference was observed among sweet and fermenting juices as well as between liver and fish. The preferences between fresh and fermenting juices were based not only on component sugars, but also on other components, namely, amino acids, alcohol salts and presumably other chemical compounds. The preference between decaying liver and fish was probably based partly on the composition and concentration of amino acids in these foods. A variety of amino acids were found in foods and some of these amino acids were shown to be excitatory, some inhibitory and others neutral. Salts were also observed to be present in the juices; and in a laboratory study NaCl at lower concentrations acted synergestically with 0.1 M sucrose and at higher concentrations repulsive. It is suggested that feeding preference is based on several chemicals which behave either in an excitatory, additive, neutral, inhibitory or synergistic manner. The ratio of excitants to inhibitants is important in deciding the direction of preference.

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Résumé P. regina Meigen mâle préfere certains aliments naturels ou artificiels. Au laboratoire ses préférences parmi les jus sucrés sont les suivantes: orange > miel > pomme > sucrose 0.1 M; et parmi les aliments en décomposition: sucrose 0.1 M > foie > poisson. Les jus frais sont préférés aux jus fermentés. Les préférences ne dépendent pas seulement de la nature des sucres, mais aussi des acides aminés, de l'alcool, des sels et probablement d'autres substances chimiques. Le foie contient à la fois le plus grand nombre et la concentration la plus élevée en acides aminés, ce qui explique partiellement le goût pour le foie. Expérimentalement on peut classer les acides aminés en stimulants, inhibiteurs et neutres. Des sels ont été notés dans les jus, mais aucune analyse qualitative et quantitative n'en a été faite. Mélangé à du sucrose à 0.1 M, NaCl agit en synergie aux faibles concentrations, devient neutre à 0.175 M et à des concentrations supérieures le sucrose seul est préféré au mélange avec NaCl. Cependant, un mélange de NaCl à 0.25 M (bien qu'une telle concentration soit peu probable dans des jus végétaux) avec du sucrose à 0.1 M était préféré à l'eau. Il en est déduit que les préférences alimentaires. dans la nature sont orientées par plusieurs substances chimiques qui se comportent d'une façon stimulante, additive, neutre, inhibitrice ou synergique, et que les préférences alimentaires sont relatives. Le rapport de stimulants sur inhibiteurs est important dans la détermination du sens de la préférence.

     

Mitochondrial Oxidative Phosphorylation Complex Regulates NLRP3 Inflammasome Activation and Predicts Patient Survival in Nasopharyngeal Carcinoma

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Highlights

• •Flow cytometry analysis is used to isolate ASC speck⁽⁺⁾ NPC cells.
• •Proteome analysis of ASC speck⁽⁺⁾ NPC cells reveals enriched mitochondrial OxPhos proteins.
• •OxPhos proteins mediate NLRP3 inflammasome activation through mtROS.
• •OxPhos proteins, NDUFB8 and ATP5B are correlated with NPC local recurrence.

     

The transient and constitutive inflammatory signaling in tumorigenesis

Comment on: Rokavec M, et al. Mol Cell 2012; 45:777-89.     

Associations of demographic and perinatal factors with childhood neuroblastoma in Texas, 1995–2011

BackgroundNeuroblastoma, the most common extracranial solid tumor in children, contributes disproportionately to childhood cancer mortality and few risk factors have been identified. Our objective was to evaluate associations between parental and infant characteristics and neuroblastoma incidence.MethodsChildren born in Texas between January 1995 and December 2011 were eligible for the present study. Cases (N = 637) were diagnosed with neuroblastoma in Texas during the same period; controls (N = 6370) matched on year of birth were randomly selected from birth certificates that did not link to a record in the Texas Cancer Registry. We obtained data on birth and parental demographic/reproductive characteristics from birth certificates, and estimated odds ratios (OR) and 95% confidence intervals (CIs) for neuroblastoma using logistic regression.ResultsGestational age 34–36 weeks at birth was associated with neuroblastoma (OR 1.45, CI 1.09–1.90), whereas female sex was inversely associated (OR 0.68, CI 0.58–0.81). Relative to children of non-Hispanic White women, children of Hispanic (OR 0.53, CI 0.43–0.64) or non-Hispanic Black (OR 0.52, CI 0.38–0.71) women were at reduced odds of neuroblastoma. When maternal and paternal race/ethnicity were evaluated jointly, similar patterns were observed (two non-Hispanic Black parents: OR 0.55, 95%CI 0.36–0.79; two Hispanic parents: OR 0.53, 95%CI 0.41–0.67). Older maternal age was also positively associated with neuroblastoma (OR 1.41, CI 1.04–1.90 for 35–39 years; OR 1.62, CI 0.87–2.81 for ≥40 years, relative to 25–29 years).ConclusionsFindings provide further evidence of racial/ethnic disparities in neuroblastoma incidence, determinants of which are unknown. In contrast to most published studies, we observed an association between maternal age and neuroblastoma. Further studies with more robust control for confounding are warranted.     

Small Molecular Inhibitors Block TRPM4 Currents in Prostate Cancer Cells,with Limited Impact on Cancer Hallmark Functions

Transient receptor potential melastatin 4 (TRPM4) is a broadly expressed Ca²⁺ activated monovalent cation channel that contributes to the pathophysiology of several diseases.For this study, we generated stable CRISPR/Cas9 TRPM4 knockout (K.O.) cells from the human prostate cancer cell line DU145 and analyzed the cells for changes in cancer hallmark functions. Both TRPM4-K.O. clones demonstrated lower proliferation and viability compared to the parental cells. Migration was also impaired in the TRPM4-K.O. cells. Additionally, analysis of 210 prostate cancer patient tissues demonstrates a positive association between TRPM4 protein expression and local/metastatic progression. Moreover, a decreased adhesion rate was detected in the two K.O. clones compared to DU145 cells.Next, we tested three novel TRPM4 inhibitors with whole-cell patch clamp technique for their potential to block TRPM4 currents. CBA, NBA and LBA partially inhibited TRPM4 currents in DU145 cells. However, none of these inhibitors demonstrated any TRPM4-specific effect in the cellular assays.To evaluate if the observed effect of TRPM4 K.O. on migration, viability, and cell cycle is linked to TRPM4 ion conductivity, we transfected TRPM4-K.O. cells with either TRPM4 wild-type or a dominant-negative mutant, non-permeable to Na⁺. Our data showed a partial rescue of the viability of cells expressing functional TRPM4, while the pore mutant was not able to rescue this phenotype. For cell cycle distribution, TRPM4 ion conductivity was not essential since TRPM4 wild-type and the pore mutant rescued the phenotype.In conclusion, TRPM4 contributes to viability, migration, cell cycle shift, and adhesion; however, blocking TRPM4 ion conductivity is insufficient to prevent its role in cancer hallmark functions in prostate cancer cells.