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Obesity impacts the regulation of miR-10b and its targets in primary breast tumors
Background
Obesity increases breast cancer (BC) risk in post-menopausal women by mostly unknown molecular mechanisms which may partly be regulated by microRNAs (miRNAs).
Methods
We isolated RNA from paired benign and malignant biopsies from 83 BC patients and determined miRNA profiles in samples from 12 women at the extremes of the BMI distribution by RNA-seq. Candidates were validated in all samples. Associations between miR-10b expression and validated target transcript levels, and effects of targeted manipulation of miR-10b levels in a primary BC cell line on proliferation and invasion potential, were explored.
Results
Of the 148 miRNAs robustly expressed in breast tissues, the levels of miR-21, miR-10b, miR-451a, miR-30c, and miR-378d were significantly associated with presence of cancer. Of these, miR-10b showed a stronger down-regulation in the tumors of the obese subjects, as opposed to the lean. In ductal but not lobular tumors, significant inverse correlations were observed between the tumor levels of miR-10b and miR-30c and the mRNA levels of cancer-relevant target genes
SRSF1, PIEZO1, MAPRE1, CDKN2A, TP-53
and
TRA2B,
as well as tumor grade
.
Suppression of miR-10b levels in BT-549 primary BC–derived cells increased cell proliferation and invasive capacity, while exogenous miR-10b mimic decreased invasion. Manipulation of miR-10b levels also inversely affected the mRNA levels of miR-10b targets
BCL2L11, PIEZO1
and
NCOR2
.
Conclusions
Our findings suggest that miR-10b may be a mediator between obesity and cancer in post-menopausal women, regulating several known cancer-relevant genes. MiR-10b expression may have diagnostic and therapeutic implications for the incidence and prognosis of BC in obese women.
Journal Article
A new species of Hypoprepia from the mountains of central Arizona (Lepidoptera, Erebidae, Arctiinae, Lithosiini)
A new firefly-mimicking lichen moth of the genus Hypoprepia , H.lampyroides Palting & Ferguson, sp. n. , is described from the mountains of east-central Arizona and the Sierra Madre Occidental of Mexico. Hypoprepia Hübner, 1831 is a North American genus of lithosiine tiger moths, previously consisting of five species: H.fucosa Hübner, 1831 and H.miniata (Kirby, 1837), both of eastern and central North America; H.cadaverosa Strecker, 1878 from the Rocky Mountains into New Mexico and west Texas; H.inculta H. Edwards, 1882, a widespread western USA species and H.muelleri Dyar, 1907 from the vicinity of Mexico City. The latter is herein synonymized under H.inculta (= H.muelleri syn. n. ), resulting in the total number of taxa in the genus unchanged at five.
Journal Article
Utilization of Raman spectroscopy to identify breast cancer from the water content in surgical samples containing blue dye
Breast conserving surgery (BCS) for breast cancer aims for optimal oncological results with minimal tissue excision. Positive margins due to insufficient resection results in significant numbers of patients requiring re‐excision, which could be resolved with intra‐operative margin analysis (IMA). High wavenumber (HWN) Raman Spectroscopy (RS) examines the difference in protein/lipid environment and water content in tissues. Fluorescence from haemoglobin and blue dye surgical pigments (commonly present in excised breast tissue) can confound HWN RS. We present a Raman system with 785 nm excitation laser and indium gallium arsenide camera capable of quantifying changes in water content in different environments (protein‐rich and lipid‐rich) by measuring the water/total area ratio (W/TAR) of the HWN spectrum. We demonstrate that haemoglobin and blue dye do not adversely affect water content analysis by the W/TAR calculation. Measurement of paired tumour/non‐tumour human breast tissue specimens showed the biochemical differences between tissues, and spectral analysis with W/TAR demonstrated large differences in water content and that our Raman system can accurately differentiate between tumour and non‐tumour tissue, even in the presence of surgical pigments. This provides proof of principle that this Raman system is suitable for further investigation with a view to providing IMA in the clinical environment. We demonstrate the biochemical differences in malignant human breast tissue and spectral analysis of water content differentiates between tumour and non‐tumour tissue, even in the presence of surgical pigments. We present a Raman system with the potential to provide IMA in the clinical environment.
Journal Article
Multiscale Model Identifies Improved Schedule for Treatment of Acute Myeloid Leukemia In Vitro With the Mcl‐1 Inhibitor AZD5991
Anticancer efficacy is driven not only by dose but also by frequency and duration of treatment. We describe a multiscale model combining cell cycle, cellular heterogeneity of B‐cell lymphoma 2 family proteins, and pharmacology of AZD5991, a potent small‐molecule inhibitor of myeloid cell leukemia 1 (Mcl‐1). The model was calibrated using in vitro viability data for the MV‐4‐11 acute myeloid leukemia cell line under continuous incubation for 72 hours at concentrations of 0.03–30 μM. Using a virtual screen, we identified two schedules as having significantly different predicted efficacy and showed experimentally that a “short” schedule (treating cells for 6 of 24 hours) is significantly better able to maintain the rate of cell kill during treatment than a “long” schedule (18 of 24 hours). This work suggests that resistance can be driven by heterogeneity in protein expression of Mcl‐1 alone without requiring mutation or resistant subclones and demonstrates the utility of mathematical models in efficiently identifying regimens for experimental exploration.
Journal Article
Most local newspapers use Pinterest only for news
This study examines how local newspapers across the USA use the social network Pinterest. News is the predominant theme in the 1,123 pin boards analyzed. Also, the number of pin boards is related to the newspapers’ circulation size. Few use Pinterest to promote the newspaper.
Journal Article
Case Study Answers Are Not Elementary: How a Positive Outlier K-5 School Beat the Odds
There are a limited number of case studies of positive outlier elementary schools, otherwise known as schools that are beating the odds, and more of such studies are needed in order to effectively replicate positive problem-solving solutions. Positive outlier schools and districts, the focus of this dissertation, are those that score significantly above demographically similar schools and districts on standardized state testing. For example, none of the existing case studies highlight organizational culture as a key factor despite the fact that many of the more targeted topically focused studies cite school culture as a top factor. Additionally, the longest running case study of a positive outlier school only covers five years of data. This study addresses both of these problems as well as several others by evaluating 10 years of data through interviews with 30 participants, inquiring specifically about culture as well as climate and leadership and numerous other variables (factors), and following up with additional in-depth interviews. The theory that most closely represents a holistic approach and therefore comes closest to addressing the data in this case study is Bronfenbrenner's Bioecological Theory of Human Development. Ultimately, more case studies of positive outlier school systems should be done because the case study is a good methodological fit for examining key variables of outlier schools. In conclusion, additional research on positive outlier school systems that is holistic in nature should be conducted via case studies, with an emphasis on expanding the literature at the elementary level.
Dissertation
On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology
The inaccessibility of living bone marrow (BM) hampers the study of its pathophysiology under myelotoxic stress induced by drugs, radiation or genetic mutations. Here, we show that a vascularized human BM-on-a-chip (BM chip) supports the differentiation and maturation of multiple blood cell lineages over 4 weeks while improving CD34
+
cell maintenance, and that it recapitulates aspects of BM injury, including myeloerythroid toxicity after clinically relevant exposures to chemotherapeutic drugs and ionizing radiation, as well as BM recovery after drug-induced myelosuppression. The chip comprises a fluidic channel filled with a fibrin gel in which CD34
+
cells and BM-derived stromal cells are co-cultured, a parallel channel lined by human vascular endothelium and perfused with culture medium, and a porous membrane separating the two channels. We also show that BM chips containing cells from patients with the rare genetic disorder Shwachman–Diamond syndrome reproduced key haematopoietic defects and led to the discovery of a neutrophil maturation abnormality. As an in vitro model of haematopoietic dysfunction, the BM chip may serve as a human-specific alternative to animal testing for the study of BM pathophysiology.
A vascularized human bone-marrow-on-a-chip improves the maintenance of patient-derived CD34
+
cells, and recapitulates clinically relevant aspects of bone marrow injury as well as key haematopoietic defects of patients with a rare genetic disorder.
Journal Article
Distribution of P2X1 and P2X3 Receptors in the Rat and Human Urinary Bladder
Adenosine 5′-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X 1 and P2X 3 , respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X 1 receptor immunoreactivity was found on detrusor muscle fibres and P2X 3 receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X 3 receptors. No clear evidence was found for the presence of P2X 3 receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X 3 receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.
Journal Article
Current axillary management of patients with early breast cancer and low-volume nodal disease undergoing primary surgery: results of a United Kingdom national practice survey
Purpose
UK NICE guidelines recommend axillary node clearance (ANC) should be performed in all patients with biopsy-proven node-positive breast cancer having primary surgery. There is, however, increasing evidence such extensive surgery may not always be necessary. Targeted axillary dissection (TAD) may be an effective alternative in patients with low-volume nodal disease who are clinically node negative (cN0) but have abnormal nodes detected radiologically. This survey aimed to explore current management of this group to inform feasibility of a future trial.
Methods
An online survey was developed to explore current UK management of patients with low-volume axillary disease and attitudes to a future trial. The survey was distributed via breast surgery professional associations and social media from September to November 2022. One survey was completed per unit and simple descriptive statistics used to summarise the results.
Results
51 UK breast units completed the survey of whom 78.5% (
n
= 40) reported performing ANC for all patients with biopsy-proven axillary nodal disease having primary surgery. Only 15.7% of units currently performed TAD either routinely (
n
= 6, 11.8%) or selectively (
n
= 2, 3.9%). There was significant uncertainty (83.7%,
n
= 36/43) about the optimal surgical management of these patients. Two-thirds (
n
= 27/42) of units felt an RCT comparing TAD and ANC would be feasible.
Conclusions
ANC remains standard of care for patients with low-volume node-positive breast cancer having primary surgery in the UK, but considerable uncertainty exists regarding optimal management of this group. This survey suggests an RCT comparing the outcomes of TAD and ANC may be feasible.
Journal Article