Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular ...transformation, metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if metformin is added after the initial inflammatory stimulus. The antitransformation effect of metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response. As metformin alters energy metabolism in diabetics, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
Metformin, the first-line drug for treating diabetes, selectively kills the chemotherapy resistant subpopulation of cancer stem cells (CSC) in genetically distinct types of breast cancer cell lines. ...In mouse xenografts, injection of metformin and the chemotherapeutic drug doxorubicin near the tumor is more effective than either drug alone in blocking tumor growth and preventing relapse. Here, we show that metformin is equally effective when given orally together with paclitaxel, carboplatin, and doxorubicin, indicating that metformin works together with a variety of standard chemotherapeutic agents. In addition, metformin has comparable effects on tumor regression and preventing relapse when combined with a four-fold reduced dose of doxorubicin that is not effective as a monotherapy. Finally, the combination of metformin and doxorubicin prevents relapse in xenografts generated with prostate and lung cancer cell lines. These observations provide further evidence for the CSC hypothesis for cancer relapse, an experimental rationale for using metformin as part of combinatorial therapy in a variety of clinical settings, and for reducing the chemotherapy dose in cancer patients.
Abstract Background In accordance with the 2007 American College of Cardiology and American Heart Association infective endocarditis (IE) guideline update, antibiotic prophylaxis is now being ...restricted to a smaller number of cardiac conditions with very high risk for adverse outcomes from IE. However, there is scant data on IE trends since this major practice change in the United States. Objectives The aim of this study was to compare temporal trends in IE incidence, microbiology, and outcomes before and after the change in the 2007 IE prophylaxis guideline in the United States. Methods The NIS (Nationwide Inpatient Sample) database was used to investigate IE hospitalization rates in the United States from 2000 through 2011. The mean annual rates of IE before and after the 2007 guideline change were compared using segmented regression analysis. Results There were 457,052 IE-related hospitalizations in the United States from 2000 to 2011, with a steady increase in incidence (p < 0.001). The trend in IE hospitalization rates from 2000 to 2007 and from 2008 to 2011 was not significantly different (p = 0.74). The increases in the number of Staphylococcus IE cases per million population during the study periods 2000 to 2007 and 2008 to 2011 were similar (p = 0.13), but Streptococcus IE hospitalization rates were significantly higher after the release of new guidelines (p = 0.002). Finally, valve replacement rates for IE steadily increased from 2000 to 2007 (p = 0.03) but showed a plateau from 2007 to 2011. Overall, there was no significant difference in the rates of valve replacement for IE before and after the release of new guideline (p = 0.23). Conclusions These results show that IE incidence has increased in the United States over the past decade. With regard to the microbiology of IE, there has been a significant rise in the incidence of Streptococcus IE since the 2007 guideline revisions. However, the rates of hospitalization and valve surgery for IE have not increased since the change in IE prophylaxis guideline in 2007.
Tumors are often heterogeneous, being composed of multiple cell types with different phenotypic and molecular properties. Cancer stem-like cells (CSCs) are a highly tumorigenic cell type found in ...developmentally diverse tumors or cancer cell lines, and they are often resistant to standard chemotherapeutic drugs. The origins of CSCs and their relationships to nonstem cancer cells (NSCCs) are poorly understood. In an inducible breast oncogenesis model, CSCs are generated from nontransformed cells at a specific time during the transformation process, but CSC formation is not required for transformation. MicroRNA profiles indicate that CSCs and NSCCs are related, but different cell types arising from a common nontransformed population. Interestingly, medium from the transformed population stimulates NSCCs to become CSCs, and conversion of NSCCs to CSCs occurs in mouse xe nog rafts. Furthermore, IL6 is sufficient to convert NSCCs to CSCs in genetically different breast cell lines, human breast tumors, and a prostate cell line. Thus, breast and prostate CSCs and NSCCs do not represent distinct epigenetic states, and these CSCs do not behave as or arise from classic stem cells. Instead, tumor heterogeneity involves a dynamic equilibrium between CSCs and NSCCs mediated by IL6 and activation of the inflammatory feedback loop required for oncogenesis. This dynamic equilibrium provides an additional rationale for combining conventional chemotherapy with metform in, which selectively inhibits CSCs.
Abstract
The size of a planet is an observable property directly connected to the physics of its formation and evolution. We used precise radius measurements from the California-
Kepler
Survey to ...study the size distribution of 2025
Kepler
planets in fine detail. We detect a factor of ≥2 deficit in the occurrence rate distribution at 1.5–2.0
. This gap splits the population of close-in (
P
< 100 days) small planets into two size regimes:
and
, with few planets in between. Planets in these two regimes have nearly the same intrinsic frequency based on occurrence measurements that account for planet detection efficiencies. The paucity of planets between 1.5 and 2.0
supports the emerging picture that close-in planets smaller than Neptune are composed of rocky cores measuring 1.5
or smaller with varying amounts of low-density gas that determine their total sizes.
A transient inflammatory signal can initiate an epigenetic switch from nontransformed to cancer cells via a positive feedback loop involving NF-κB, Lin28, let-7, and IL-6. We identify differentially ...regulated microRNAs important for this switch and putative transcription factor binding sites in their promoters. STAT3, a transcription factor activated by IL-6, directly activates miR-21 and miR-181b-1. Remarkably, transient expression of either microRNA induces the epigenetic switch. MiR-21 and miR-181b-1, respectively, inhibit PTEN and CYLD tumor suppressors, leading to increased NF-κB activity required to maintain the transformed state. These STAT3-mediated regulatory circuits are required for the transformed state in diverse cell lines and tumor growth in xenografts, and their transcriptional signatures are observed in colon adenocarcinomas. Thus, STAT3 is not only a downstream target of IL-6 but, with miR-21, miR-181b-1, PTEN, and CYLD, is part of the positive feedback loop that underlies the epigenetic switch that links inflammation to cancer.
► Identification of differentially regulated microRNAs during transformation ► STAT3 activates miR-21 and miR-181b-1, which target PTEN and CYLD ► Transient expression of miR-21 or miR-181b-1 induces stable transformation ► STAT3-induced pathway in the epigenetic switch linking inflammation to cancer
Abstract
We have established precise planet radii, semimajor axes, incident stellar fluxes, and stellar masses for 909 planets in 355 multi-planet systems discovered by
Kepler
. In this sample, we ...find that planets within a single multi-planet system have correlated sizes: each planet is more likely to be the size of its neighbor than a size drawn at random from the distribution of observed planet sizes. In systems with three or more planets, the planets tend to have a regular spacing: the orbital period ratios of adjacent pairs of planets are correlated. Furthermore, the orbital period ratios are smaller in systems with smaller planets, suggesting that the patterns in planet sizes and spacing are linked through formation and/or subsequent orbital dynamics. Yet, we find that essentially no planets have orbital period ratios smaller than 1.2, regardless of planet size. Using empirical mass–radius relationships, we estimate the mutual Hill separations of planet pairs. We find that 93% of the planet pairs are at least 10 mutual Hill radii apart, and that a spacing of ∼20 mutual Hill radii is most common. We also find that when comparing planet sizes, the outer planet is larger in 65% ± 0.4% of cases, and the typical ratio of the outer to inner planet size is positively correlated with the temperature difference between the planets. This could be the result of photo-evaporation.
Determining the potential for malignant transformation of oral lichen planus (OLP) is complicated by difficulties in diagnosis, differentiation from oral lichenoid lesions (OLLs) and the phenomenon ...of premalignant lesions' exhibiting lichenoid characteristics. The authors of this systematic review evaluated evidence regarding malignant transformation of OLP and characterized transformation prevalence, clinical characteristics of OLP lesions developing into squamous cell carcinoma (SCC) and time to transformation.
The authors searched PubMed, Embase and Thomson Reuters Web of Science in a systematic approach. They evaluated observational English-language studies involving human participants published in peer-reviewed journals. Inclusion required patients to have the diagnosis of OLP or OLL as confirmed with biopsy results on initial enrollment. They excluded all patients who had dysplasia on initial biopsy of OLP or OLL lesions.
Sixteen studies were eligible. Among 7,806 patients with OLP, 85 developed SCC. Among 125 patients with OLL, four developed SCC. The rate of transformation in individual studies ranged from 0 to 3.5 percent. The overall rate of transformation was 1.09 percent for OLP; in the solitary study in which investigators evaluated OLL, the rate of transformation was 3.2 percent. Patients' average age at onset of SCC was 60.8 years. The authors noted a slight predominance of female patients among those who experienced malignant transformation. The most common subsite of malignant transformation was the tongue. The average time from diagnosis of OLP or OLL to transformation was 51.4 months.
A small subset of patients with a diagnosis of OLP eventually developed SCC. The most common demographic characteristics of patients in this subset were similar to the most common demographic characteristics associated with OLP in general (that is, being female, being older and being affected in areas common to this condition). It is prudent for clinicians to pursue continued regular observation and follow-up in patients with these conditions, even in patients who do not fit a traditional high-risk category for oral SCC.
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