Breast calcifications following electrical defibrillation: An unusual mammographic appearance

We present a case of a 57-year-old woman with a past medical history of end-stage renal disease and a recent history of electrical defibrillation who arrived for her annual mammogram with no breast-related complaints. The mammogram showed interval development of unusual clusters of heterogeneous calcifications. The patient underwent stereotactic core-needle biopsy for definitive diagnosis. The pathologic evaluation revealed fibrosis, abnormal adipocytes, and calcifications with no evidence of malignancy. The constellation of findings was consistent with fat necrosis and fibrosis related to tissue damage sustained during the recent defibrillation

Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure

We previously reported that stable transfection of protein kinase C alpha (PKCα) into T47D human breast cancer cells results in tamoxifen (TAM)-resistant tumour growth. Relevance of PKCα expression in clinical specimens was determined by comparing PKCα expression in tumours from patients exhibiting disease recurrence with patients remaining disease-free following TAM treatment. Our results suggest that PKCα expression may predict TAM treatment failure

Frequency of post-stroke pneumonia: Systematic review and meta-analysis of observational studies

Background: Post-stroke pneumonia and other infectious complications are serious conditions whose frequency varies widely across studies. Aims: We conducted a systematic review to estimate the frequency of post-stroke pneumonia and other types of major infection. Summary of review: MEDLINE, EMBASE, CINAHL, and PsycINFO databases were searched for prospective studies with consecutive recruitment of stroke patients. The primary outcome was post-stroke pneumonia. Secondary outcomes were any infection and urinary tract infection. Quality assessment was done using Newcastle Ottawa scale. Heterogeneity of estimates across study populations was calculated using Cochran's Q (heterogeneity χ2) and I2 statistics. A total of 47 studies (139,432 patients) with 48 sample populations were eligible for inclusion. Mean age of patients was 68.3 years and their mean National Institute of Health Stroke Scale score was 8.2. The pooled frequency of post-stroke pneumonia was 12.3% (95% confidence interval [CI] 11%–13.6%; I2 = 98%). The pooled frequency from 2011 to 2017 was 13.5% (95% CI 11.8%–15.3%; I2 = 98%) and comparable with earlier periods (P interaction = 0.31). The pooled frequency in studies in stroke units was 8% (95% CI 7.1%–9%; I2 = 78%) and significantly lower than other locations (P interaction = 0.001). The pooled frequency of post-stroke infection was 21% (95% CI 13%–29.3%; I2 = 99%) and of post-stroke urinary tract infection was 7.9% (95% CI 6.7%–9.3%; I2 = 96%). Conclusion: Approximately 1 in 10 stroke patients experience pneumonia during the acute period of hospital care. The frequency of post-stroke pneumonia has remained stable in recent decades but is lower in patients receiving stroke unit care compared to management in other ward settings

Single-cell screening and quantification of transcripts in cancer tissues by second-harmonic generation microscopy

Fluorescence-based single molecule techniques to interrogate gene expression in tissues present a very low signal-to-noise ratio due to the strong autofluorescence and other background signals from tissue sections. This report presents a background-free method using second-harmonic generation (SHG) nanocrystals as probes to quantify the messenger RNA (mRNA) of human epidermal growth receptor 2 (Her2) at single molecule resolution in specific phenotypes at single-cell resolution directly in tissues. Coherent SHG emission from individual barium titanium oxide (BTO) nanoprobes was demonstrated, allowing for a stable signal beyond the autofluorescence window. Her2 surface marker and Her2 mRNA were specifically labeled with BTO probes, and Her2 mRNA was quantified at single copy sensitivity in Her2 expressing phenotypes directly in cancer tissues. Our approach provides the first proof of concept of a cross-platform strategy to probe tissues at single-cell resolution in situ

Effects of ischaemic conditioning on major clinical outcomes in people undergoing invasive procedures: systematic review and meta-analysis.

OBJECTIVE:  To summarise the benefits and harms of ischaemic conditioning on major clinical outcomes in various settings. DESIGN:  Systematic review and meta-analysis. DATA SOURCES:  Medline, Embase, Cochrane databases, and International Clinical Trials Registry platform from inception through October 2015. STUDY SELECTION:  All randomised controlled comparisons of the effect of ischaemic conditioning on clinical outcomes were included. DATA EXTRACTION:  Two authors independently extracted data from individual reports. Reports of multiple intervention arms were treated as separate trials. Random effects models were used to calculate summary estimates for all cause mortality and other pre-specified clinical outcomes. All cause mortality and secondary outcomes with P<0.1 were examined for study quality by using the GRADE assessment tool, the effect of pre-specified characteristics by using meta-regression and Cochran C test, and trial sequential analysis by using the Copenhagen Trial Unit method. RESULTS:  85 reports of 89 randomised comparisons were identified, with a median 80 (interquartile range 60-149) participants and median 1 (range 1 day-72 months) month intended duration. Ischaemic conditioning had no effect on all cause mortality (68 comparisons; 424 events; 11 619 participants; risk ratio 0.96, 95% confidence interval 0.80 to 1.16; P=0.68; moderate quality evidence) regardless of the clinical setting in which it was used or the particular intervention related characteristics. Ischaemic conditioning may reduce the rates of some secondary outcomes including stroke (18 trials; 5995 participants; 149 events; risk ratio 0.72, 0.52 to 1.00; P=0.048; very low quality evidence) and acute kidney injury (36 trials; 8493 participants; 1443 events; risk ratio 0.83, 0.71 to 0.97; P=0.02; low quality evidence), although the benefits seem to be confined to non-surgical settings and to mild episodes of acute kidney injury only. CONCLUSIONS:  Ischaemic conditioning has no overall effect on the risk of death. Possible effects on stroke and acute kidney injury are uncertain given methodological concerns and low event rates. Adoption of ischaemic conditioning cannot be recommended for routine use unless further high quality and well powered evidence shows benefit

Sex differences in chronic kidney disease prevalence in Asia: A systematic review and meta-analysis

Background: Previous reports on the prevalence of chronic kidney disease (CKD) in Asia have suggested important sex disparities but have been inconsistent in nature. We sought to synthesize available sex-disaggregated CKD prevalence data in Asia to quantify sex disparities in the region. Methods: We systematically searched MEDLINE and Embase for observational studies involving ≥500 adults who reported sex-disaggregated CKD prevalence data in any of the 26 countries in East, Southeast and South Asia. For each study we calculated the female:male prevalence ratio (PR), with a ratio >1 indicating a higher female prevalence. For each country, log-transformed PRs were pooled using random effects meta-analysis. These were then combined using a fixed effects model, weighting by population size, to estimate a pooled PR for each of East, Southeast and South Asia and Asia overall. Results: Sex-disaggregated data were available from 171 cohorts, spanning 15 countries and comprising 2 550 169 females and 2 595 299 males. Most studies (75.4%) came from East Asia (China, Taiwan, Japan and South Korea). Across Asia, CKD prevalence was higher in females {pooled prevalence 13.0% [95% confidence interval (CI) 11.3-14.9]} compared with males [pooled prevalence 12.1% (95% CI 10.3-14.1)], with a pooled PR of 1.07 (95% CI 0.99-1.17). Substantial heterogeneity was observed between countries. The pooled PRs for East, Southeast and South Asia were 1.11 (95% CI 1.02-1.21), 1.09 (0.88-1.36) and 1.03 (0.87-1.22), respectively. Conclusions: Current evidence suggests considerable between-country and-region heterogeneity in the female:male PR of CKD. However, there remains a large part of the region where data on sex-specific CKD prevalence are absent or limited. Country-level assessment of the differential burden of CKD in females and males is needed to define locally relevant policies that address the needs of both sexes

NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT

The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities

Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells

Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF-κB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically

Differential gene expression profiling of esophageal adenocarcinoma

BackgroundDifferential gene expression offers an attractive means by which to study genes that may be involved in disease development and/or progression. We performed quantitative gene expression in various stages of esophageal adenocarcinoma, treated exclusively by surgery with complete 2-field lymphadenectomy, in an attempt to discern genes involved in disease progression as well as genes that may predict survival.MethodsGene expression profiling was accomplished by cDNA-mediated annealing, selection, extension, and ligation (DASL) assay. RNA was extracted from 89 archived formalin-fixed, paraffin-embedded esophageal adenocarcinoma tissues. DASL assay was performed with the Sentrix Universal Array (Illumina Corp, San Diego, Calif) of 502 known cancer-related genes. Bioinformatics tools were used to determine significant differential gene expression in T1-2 versus T3-4 tumors and tumors without lymph node involvement (N0) versus tumors with lymph node involvement (N+). Gene expression was also correlated with overall survival.ResultsTwenty-one genes were overexpressed in T1-2 compared with T3-4 tumors (false discovery rate of 0). Underexpression of 1 gene was seen in N+ compared with N0 tumors (false discovery rate of 0). For overall survival, underexpression of 9 genes correlated with long survival.ConclusionsUsing differential gene expression of 502 known cancer genes, we identified genes that may be involved at various stages in the progression of esophageal adenocarcinoma. We also identified genes that may correlate with prolonged survival and, thus, may serve as prognostic markers. These findings may provide further insight into the mechanisms of development and/or progression of esophageal adenocarcinoma. Prospective studies are needed to verify the prognostic value of these genes