Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells

Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours

Relapse after treatment withdrawal of antiepileptic drugs for juvenile absence epilepsy and juvenile myoclonic epilepsy

Purpose Conventional teaching is that juvenile myoclonic epilepsy (JME) and juvenile absence epilepsy (JAE) require lifelong antiepileptic drug (AED) treatment. We therefore wanted to determine how many patients attending our epilepsy service with JAE or JME went into 2 year remission, and then relapsed, both off and on AEDs. Method This was a retrospective case-notes review. Patients with JAE and JME were systematically ascertained from clinic lists and databases at one teaching hospital. Data was extracted systematically. Simple descriptive statistics were used. Results JAE: 14/36 (39%) were seizure free on AEDs for at least 2 years. Of the 6 (43%) attempting AED withdrawal, all (100%) relapsed, compared with only 25% of those who did not withdraw AEDs. Only 2/5 who relapsed and restarted AEDs regained remission. JME: 32/145 (22%) were seizure free on AEDs for at least 2 years. Of the 10 (31%) attempting AED withdrawal, 8 (80%) relapsed, compared with only 36% of those who did not withdraw AEDs. Only 2/8 who relapsed and restarted AEDs regained remission. Conclusion Remission rates for JAE and JME was lower than expected. Higher proportions of seizure free patients underwent physician-supervised withdrawal than anticipated. Relapse rates off AEDs were similar for JAE and JME, and at least twice as high as for those remaining on AEDs, and a further remission was not invariable on restarting AEDs. Our experience, comparing relapse in those withdrawing to those staying on AEDs will help in discussions with patients keen to try AED withdrawal

Genome-Wide Analyses of Nkx2-1 Binding to Transcriptional Target Genes Uncover Novel Regulatory Patterns Conserved in Lung Development and Tumors

The homeodomain transcription factor Nkx2-1 is essential for normal lung development and homeostasis. In lung tumors, it is considered a lineage survival oncogene and prognostic factor depending on its expression levels. The target genes directly bound by Nkx2-1, that could be the primary effectors of its functions in the different cellular contexts where it is expressed, are mostly unknown. In embryonic day 11.5 (E11.5) mouse lung, epithelial cells expressing Nkx2-1 are predominantly expanding, and in E19.5 prenatal lungs, Nkx2-1-expressing cells are predominantly differentiating in preparation for birth. To evaluate Nkx2-1 regulated networks in these two cell contexts, we analyzed genome-wide binding of Nkx2-1 to DNA regulatory regions by chromatin immunoprecipitation followed by tiling array analysis, and intersected these data to expression data sets. We further determined expression patterns of Nkx2-1 developmental target genes in human lung tumors and correlated their expression levels to that of endogenous NKX2-1. In these studies we uncovered differential Nkx2-1 regulated networks in early and late lung development, and a direct function of Nkx2-1 in regulation of the cell cycle by controlling the expression of proliferation-related genes. New targets, validated in Nkx2-1 shRNA transduced cell lines, include E2f3, Cyclin B1, Cyclin B2, and c-Met. Expression levels of Nkx2-1 direct target genes identified in mouse development significantly correlate or anti-correlate to the levels of endogenous NKX2-1 in a dosage-dependent manner in multiple human lung tumor expression data sets, supporting alternative roles for Nkx2-1 as a transcriptional activator or repressor, and direct regulator of cell cycle progression in development and tumors

Disease modifiers, mechanisms and monitoring in CADASIL

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Photometric determination of copper(II) by adsorption of its 1-phenyl- 3( 2-thiazolyl) thiourea complex on polyurethane foam

453-454Adsorption of I-phenyl-3-(2-thiazolyl) thiourea-copper( II) complex on polyurethane foam has been studied and a new method is described for the photometric determination of copper(II). The complex can be extracted into chloroform and it has λmax at465 nm. The absorbance shows a linear relationship over the concentration range 10-100 mg Cu(II) in 10 ml chloroform. The molar absorptivity and sensitivity are found to be 1.37 x 104 1 mol-1 cm-1 and 0.014 mg cm-2 of Cu(II) for 0.001 absorbance respectively. The .method has been successfully applied for the estimation of micro amounts of copper(II) in alloys

Photometric determination of vanadium(V) after adsorption of its schiff's base (derived from 2-aminopyridine and naphthalene-1-carbaldehyde) complex on polyurethane foam

455-456The absorbance of vanadium(V) complex of schiff's base derived from 2-aminopyridine and naphthalenel- carbaldehyde after prelintinary adsorption of polyurethane foam has been studied. It is found that Beer's law is obeyed over the concentration range 1085 mg of vanadium(V) in 10 ml chloroform. Molar absorptivity and sensitivity are calculated to be 6.6 x 104 1 mol-1 cm-1 and 0.061 mg cm-2 of V(V) respectively at 495 nm. The effects of pH, reagent concentration, absorbent, diverse metal ions on photometric determination of vanadium have been studied. The method has been applied satisfactorily for determination of vanadium in OHNS steel alloy sample

Photometric determination of uranium(VI) with 1-phenyl- 3-(2-thiazolyl)thiourea after preliminary adsorption on polyurethane foam

809-810The photometric determination of uranium(VI) with 1-phenyl-3-(2-thiazolyl)thiourea using polyurethane foam as adsorbent has been discussed. Beer's law is obeyed over the concentration range 10-170 µg of U(VI) in 10 ml chloroform. Molar absorptivity and sensitivity are found to be 3.56 x 104 l.mol-1 cm- 1 and 0.019 µg cm-2 of U(VI) for 0.001 absorbance respectively

Diffusion tensor imaging of thalamus correlates with cognition in CADASIL without dementia.

Abnormalities of normal-appearing white and deep gray matter are present in nondemented CADASIL patients, and these DTI measurements correlate particularly strongly with executive function

A comparative study of the adverse effects due to use of N95 and cloth mask

Introduction: Covid -19 infection spread rapidly from person to person. Social distancing, hygiene and mask are among various preventive measures for spread of this infection Prolonged use of N95 and surgical masks causes physical adverse effects such as headaches, difficulty breathing, acne, skin breakdown, rashes, and impaired cognition. Some facial masks are secured by anchoring to the ears, causing damage to the external ears and retroauricular skin areas because of pressure, prolonged exposure, or both. Methods: This was questionnaire bases study. Questionnaire was distributed to participants. 200 N95 mask wearer and 200 cloth mask wearers were included in study. Results: Dermatological adverse effects were more in participants wearing N95 mask. Also, N95 mask wearer have to speak louder during conversation. There is statistically significant between N95 and cloth wearer in terms of dermatological and speech difficulties. Conclusion: Mask prevents spread of covid- 19 infection from person to person. There are many adverse effects of masks. In view of adverse effect related to skin and speech difficulty cloth mask is better