High dietary iron has been linked to an increased type 2 diabetes risk. We have previously shown that intrauterine growth restriction (IUGR) and feeding a Western diet (WD) to male Sprague-Dawley ...rats independently, as well as together, cause pancreatic islet inflammation, fibrosis, and hemosiderosis.
To investigate whether iron has a role in the pathogenesis of this inflammatory islet injury caused by IUGR and WD intake.
Male Sprague-Dawley offspring of bilateral uterine artery ligated (IUGR) and sham-operated (Sham) dams, fostered to nonoperated dams, were fed a WD 45% sucrose, 19.4% protein and 23% fat (w/w) containing low iron (LI, 20 mg/kg) or high iron (HI, 500 mg/kg) from weaning. Four groups were studied: Sham-LI, Sham-HI, IUGR-LI, and IUGR-HI. Serial measurements of rat body weight, blood glucose, lipids and insulin, an intraperitoneal glucose tolerance test (age 13 wk), and histological analysis of pancreas and liver (age 14 wk) were recorded. The effects of iron, IUGR, and their interaction, on these measurements have been analyzed.
WD with HI compared with LI caused an 11% greater weight gain by age 14 wk (P < 0.001), impaired glucose tolerance AUC for glucose (G-AUC) 17% higher; P < 0.001), acute pancreatitis (17/18, HI; 6/17, LI; P < 0.001), pancreas-associated fat necrosis and saponification (7/18, HI; 0/17 LI; P < 0.01), and a trend to islet fibrotic injury (7/18, HI; 1/17 LI; P = 0.051). Although pancreatic and hepatic steatosis was evident in almost all WD-fed rats, pancreatic and hepatic iron accumulation was prevalent only in HI-fed rats (P < 0.0001 for both), being only mild in the livers. IUGR, independent of dietary iron, also caused impairment in glucose tolerance (G-AUC: 17% higher; P < 0.05).
A postweaning WD containing HI, independent of IUGR, causes acute pancreatitis and islet injury in Sprague-Dawley rats suggesting a role of dietary iron in the development of steatopancreatitis.
Testis‐specific regulators of chromatin function are commonly ectopically expressed in human cancers, but their roles are poorly understood. Examination of 81 primary Hodgkin lymphoma (HL) samples ...showed that the ectopic expression of the eutherian testis‐specific histone variant H2A.B is an inherent feature of HL. In experiments using two HL cell lines derived from different subtypes of HL, H2A.B knockdown inhibited cell proliferation. H2A.B was enriched in both nucleoli of these HL cell lines and primary HL samples. We found that H2A.B enhanced ribosomal DNA (rDNA) transcription, was enriched at the rDNA promoter and transcribed regions, and interacted with RNA Pol I. Depletion of H2A.B caused the loss of RNA Pol I from rDNA chromatin. Remarkably, H2A.B was also required for high levels of ribosomal protein gene expression being located at the transcriptional start site and within the gene body. H2A.B knockdown reduced gene body chromatin accessibility of active RNA Pol II genes concurrent with a decrease in transcription. Taken together, our data show that in HL H2A.B has acquired a new function, the ability to increase ribosome biogenesis.
SYNOPSIS
The eutherian testis‐specific histone variant H2A.B is aberrantly expressed in Hodgkin Lymphoma and enhances ribosomal biogenesis by stimulating both RNA Pol I transcription and the transcription of ribosomal protein genes.
H2A.B is required for the high cell proliferation rate of Hodgkin Lymphoma cell lines.
H2A.B is enriched in rDNA chromatin and interacts with RNA Pol I.
H2A.B is required for transcription and alternative splicing of genes that are linked to cancer such as ribosomal proteins.
The chromatin accessibility of active genes is enhanced by H2A.B.
The eutherian testis‐specific histone variant H2A.B is aberrantly expressed in Hodgkin Lymphoma and enhances ribosomal biogenesis by stimulating both RNA Pol I transcription and the transcription of ribosomal protein genes.
Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a ...novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin.
During normal human kidney development, nephrogenesis (the formation of nephrons) is complete by term birth, with the majority of nephrons formed late in gestation. The aim of this study was to ...morphologically examine nephrogenesis in fetal human kidneys from 20 to 41weeks of gestation.
Kidney samples were obtained at autopsy from 71 infants that died acutely in utero or within 24h after birth. Using image analysis, nephrogenic zone width, the number of glomerular generations, renal corpuscle cross-sectional area and the cellular composition of glomeruli were examined. Kidneys from female and male infants were analysed separately.
The number of glomerular generations formed within the fetal kidneys was directly proportional to gestational age, body weight and kidney weight, with variability between individuals in the ultimate number of generations (8 to 12) and in the timing of the cessation of nephrogenesis (still ongoing at 37weeks gestation in one infant). There was a slight but significant (r2=0.30, P=0.001) increase in renal corpuscle cross-sectional area from mid gestation to term in females, but this was not evident in males. The proportions of podocytes, endothelial and non-epithelial cells within mature glomeruli were stable throughout gestation.
These findings highlight spatial and temporal variability in nephrogenesis in the developing human kidney, whereas the relative cellular composition of glomeruli does not appear to be influenced by gestational age.
•There is spatial and temporal variability in nephrogenesis in the developing human kidney.•The relative cellular composition of mature glomeruli does not appear to be influenced by gestational age.•There is apparent sexual dimorphism in the growth of glomeruli during late gestation.
The number of glomeruli (filtering units of the kidneys) you are born with directly influences your life-long kidney health, therefore it is important to understand how they are formed. Between mid-pregnancy and term, there was variability between individuals in relation to the number of layers of glomeruli formed in the developing kidney, and variation in the timing of when they stopped being formed. In fully-formed glomeruli, the proportion of the different cell types in glomeruli remained constant within the developing kidneys throughout pregnancy. Female infants, but not males, exhibited an increase in the size of glomeruli from mid-pregnancy to term.
Evidence suggests recent improvements in outcome in early breast cancer (EBC).
To analyse recurrence in women with EBC from our region from 1997 to 2015.
We analysed recurrence in 3,765 women with ...EBC. Median follow up was 83·0 months. 62·5% had a symptomatic presentation. 81·8% were hormone receptor positive and 38·5% were node positive. Lymphovascular invasion (LVI) was present in 24·3%. Of the 2,686 women entered from 2002 onwards tested for HER2 status, 72·7% had a luminal tumour, 15·2% had a HER2+ tumour and 12·1% had a triple negative (TN) tumour.
Recurrence occurred in 459 (12·2%), predominantly in distant sites (71·7%). In women entered from 2002 onwards, the five and 10 year recurrence rates were significantly lower in the luminal group than the HER2+ and the TN groups. Few recurrences occurred in HER2+ and TN cancers after 36 months. On multivariate analysis the following were associated with a significantly increased risk of recurrence: nodal involvement (p < 0·0001), tumour grade (p < 0·0001), symptomatic presentation (p < 0·0001), presence of LVI (p = 0·001), non-luminal tumour type (p < 0·0001) and tumour size >50 mm (p = 0·02).
The recurrence rate in this series was much lower than in previous older series. Lymph node involvement, tumour grade, symptomatic presentation, presence of LVI, non-luminal tumour type and tumour size (>50 mm) were associated with an increased risk of recurrence. We strongly recommend that clinicians include the presence of LVI and symptomatic presentation as well as the other established tumour factors, when assessing the risk of recurrence in women with EBC.
•We analysed recurrence in 3,765 Australian women with early breast cancer, treated between 1997–2015 with a median follow up of 83 months.•Recurrence occurred in 459 (12.2%), predominantly in distant sites.•Recurrence rates were significantly lower in the luminal than the HER2+ and triple negative groups.•Nodal involvement, tumour grade, symptomatic presentation, lymphovascular invasion, negative tumour hormone receptor status and tumour size were associated with recurrence.
Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical ...for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1
CD8
T cells from resistant melanoma patients and 4T1 immunotherapy-resistant mice. Targeting the LSD1p nuclear axis induces IFN-γ/TNF-α-expressing CD8
T cell infiltration into the tumors of 4T1 immunotherapy-resistant mice, which is further augmented by combined immunotherapy. Underpinning these observations, nLSD1p is regulated by the key T cell exhaustion transcription factor EOMES in dysfunctional CD8
T cells. EOMES co-exists with nLSD1p in PD-1
CD8
T cells in resistant patients, and nLSD1p regulates EOMES nuclear dynamics via demethylation/acetylation switching of critical EOMES residues. Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.
Long interspersed nuclear element 1 (LINE-1) retrotransposons are mutagens that are capable of generating deleterious mutations by inserting themselves into genes and affecting gene function in the ...human genome. In normal cells, the activity of LINE-1 retrotransposon is mostly repressed, maintaining a stable genome structure. In contrast, cancer cells are characterized by aberrant expression of LINE-1 retrotransposons, which, in principle, have the potential to contribute to genomic instability. The mechanistic pathways that regulate LINE-1 expression remain unclear. Using deep-sequencing small RNA analysis, we identified a subset of differentially expressed endo-siRNAs that directly regulate LINE-1 expression. Detailed analyses suggest that these endo-siRNAs are significantly depleted in human breast cancer cells compared with normal breast cells. The overexpression of these endo-siRNAs in cancer cells markedly silences endogenous LINE-1 expression through increased DNA methylation of the LINE-1 5′-UTR promoter. The finding that endo-siRNAs can silence LINE-1 activity through DNA methylation suggests that a functional link exists between the expression of endo-siRNAs and LINE-1 retrotransposons in human cells.
Fetal growth restriction (FGR) affects about 5-10% pregnancies and is associated with poorer outcomes in the perinatal period. Additionally, long standing epidemiological data support its association ...with chronic diseases such as hypertension and diabetes. Cardiac and vascular adaptations in response to chronic hypoxemia due to utero-placental insufficiency are hallmarks of fetal adaptations. Investigators have attempted to identify these changes in the placenta at the microscopic and molecular level. The ex vivo dual perfusion model of the placenta enables the study of placental haemodynamics in growth-restricted pregnancies. Persistent arterial abnormalities (thickness and stiffness) noted on vascular ultrasound during fetal life through to the young-adult age group for those affected by FGR, seem to be a plausible link between in utero events and chronic circulatory diseases. Using these, this review reflects current thought on vascular maladaptive changes in the FGR cohorts and the role in investigating current and future therapeutics.
Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in ...targeted and immune‐directed therapies for other solid organ malignancies. Poly (ADP‐ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair‐deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death‐ligand 1 (PD‐L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death‐1 (PD‐1)/PD‐L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine‐specific histone demethylase‐1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine‐specific histone demethylase‐1A inhibitors or histone deacetylase inhibitors with PARPi/anti‐PD‐1/PD‐L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
Poly (ADP‐ribose) polymerase inhibitors are effective anticancer drugs that produce good initial clinical response. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Addition of epigenetic drugs and checkpoint inhibitors is a novel, potentially synergistic strategy for priming tumors and overcoming PARP inhibitor resistance.
Long interspersed nuclear element 1 (L1) belongs to a family of retrotransposons. Expression of the normally repressed L1 retrotransposons has been shown to induce genome instability by creating DNA ...double-stranded breaks and chromosomal rearrangements through the process of retrotransposition. At present, little is known about the expression of L1-encoded ORF1p and ORF2p which are indispensable for its retrotransposition activity. Given its potentially harmful effects on the genome, we investigated the implications of both ORF1p and ORF2p expression and their subcellular localization in a range of breast cancer cell lines and breast tumor tissues including 15 normal breast tissues, 25 fibroadenomas, 25 ductal carcinomas in situ (DCIS), and 95 invasive cancers. Clinicopathologic parameters and survival outcomes were investigated in association with the cytoplasmic and nuclear expression of ORF1p and ORF2p using univariate and multivariate analysis. High cytoplasmic expression of ORF1p and ORF2p was seen in DCIS tumors, but they were not related with survival outcome. The majority of invasive cancers were found to express both ORF1p and ORF2p in the cytoplasm, while nuclear expression was also seen in a subclass of those invasive cancers in the range of 28–31 %. Tumors with high nuclear expression of ORF1p and ORF2p were more significantly associated with lymph node metastasis (
p
= 0.001) and the worst patient survival (
p
< 0.0001) than those with cytoplasmic expression. This is the first study examining the effects of both ORF1p and ORF2p expression in breast cancer tissues. Our observation shows altered expression patterns of ORF1p and ORF2p within invasive cancers, which are related to differences in overall patient survival. The differing patterns of both cytoplasmic and nuclear ORF1p and ORF2p expression indicate that further studies of the biology and function of L1 retrotransposons are required in breast cancer.
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