A novel regulator of the p53-mediated mitochondrial apoptotic pathway

The p53 tumor suppressor protein induces apoptosis in response to genotoxic and environmental stress. Recent studies have revealed the existence of a transcription-independent mitochondrial p53 apoptosis pathway, however the mechanism regulating p53 translocation to mitochondria and subsequent initiation of apoptosis was not known. Here, we show that Tid1, also known as mtHsp40 or Dnaja3, interacts with p53 and directs its translocation to mitochondria in cells exposed to hypoxia. Overexpression of Tid1 in tumor cells promoted mitochondrial localization of both wildtype and mutant forms of p53 and was able to restore the pro-apoptotic activity of mutant p53 proteins that were otherwise unable to induce apoptosis. Tid1's mitochondrial signal sequence and DnaJ domain were both required for the movement of the p53-Tid1 complex from the cytosol to the mitochondria. Our findings establish Tid1 as a novel regulator of p53 localization and apoptotic function

Obsessive-Compulsive Behavior Disappearing after Left Capsular Genu Infarction

This case report describes a 74-year-old woman with obsessive-compulsive behaviors that disappeared following a left capsular genu infarction. The patient's capsular genu infarction likely resulted in thalamocortical disconnection in the cortico-basal ganglia-thalamocortical loop, which may have caused the disappearance of her obsessive-compulsive symptoms. The fact that anterior capsulotomy has been demonstrated to be effective for treating refractory obsessive-compulsive disorder further supports this hypothesis

Eukaryotic initiation factor 5B (eIF5B) regulates temozolomide-mediated apoptosis in brain tumor stem cells (BTSCs)

Permission to archive accepted author manuscriptGlioblastoma multiforme (GBM) is among the deadliest cancers, owing in part to complex inter- and intra-tumor heterogeneity and the presence of a population of stem-like cells called brain tumor stem cells (BTSCs/BTICs). These cancer stem cells survive treatment and confer resistance to the current therapies—namely, radiation and the chemotherapeutic, temozolomide (TMZ). TMZ induces cell death by alkylating DNA, and BTSCs resist this mechanism via a robust DNA damage response. Hence, recent studies aimed to sensitize BTSCs to TMZ using combination therapy, such as inhibition of DNA repair machinery. We have previously demonstrated in established GBM cell lines that eukaryotic initiation factor 5B (eIF5B) promotes the translation of pro-survival and anti-apoptotic proteins. Consequently, silencing eIF5B sensitizes these cells to TRAIL-induced apoptosis. However, established cell lines do not always recapitulate the features of human glioma. Therefore, we investigated this mechanism in patient-derived BTSCs. We show that silencing eIF5B leads to increased TMZ sensitivity in two BTSC lines, BT25 and BT48. Depletion of eIF5B decreases levels of anti-apoptotic proteins in BT48 and sensitizes these cells to TMZ-induced activation of caspase-3, cleavage of PARP, and apoptosis. We suggest that eIF5B represents a rational target to sensitize GBM tumors to the current standard-of-care.Ye

Epidermal Cysts in a Tacrolimus Treated Renal Transplant Recipient

Tacrolimus, a calcineurin inhibitor, formerly also known as FK506, is a macrolactam drug isolated from Streptomyces tsukubaensis. Its mode of action closely parallels the action of cyclosprorin A (CsA) and can be used for the treatment of inflammatory and autoimmune skin diseases in which systemic CsA has proved effective against psoriasis, pyoderma gangrenosum, atopic dermatitis, lupus erythematosus and graft versus host disease (GVHD). Although several cases of epidermal cysts have been reported in patients using cyclosporine and other immunosuppressants after organ transplantation; such types of cases have yet not been reported after administration of tacrolimus. However, we report herein a case of presence of multiple, various sized epidermal cysts in a renal transplant recipient receiving tacrolimus

Chiral self-sorted multifunctional supramolecular biocoordination polymers and their applications in sensors

Chiral supramolecules have great potential for use in chiral recognition, sensing, and catalysis. Particularly, chiral supramolecular biocoordination polymers (SBCPs) provide a versatile platform for characterizing biorelated processes such as chirality transcription. Here, we selectively synthesize homochiral and heterochiral SBCPs, composed of chiral naphthalene diimide ligands and Zn ions, from enantiomeric and mixed R-ligands and S-ligands, respectively. Notably, we find that the chiral self-sorted SBCPs exhibit multifunctional properties, including photochromic, photoluminescent, photoconductive, and chemiresistive characteristics, thus can be used for various sensors. Specifically, these materials can be used for detecting hazardous amine materials due to the electron transfer from the amine to the SBCP surface and for enantioselectively sensing a chiral species naproxen due to the different binding energies with regard to their chirality. These results provide guidelines for the synthesis of chiral SBCPs and demonstrate their versatility and feasibility for use in various sensors covering photoactive, chemiresistive, and chiral sensors

An accurate method for quantifying and analyzing copy number variation in porcine KIT by an oligonucleotide ligation assay

<p>Abstract</p> <p>Background</p> <p>Aside from single nucleotide polymorphisms, copy number variations (CNVs) are the most important factors in susceptibility to genetic disorders because they affect expression levels of genes. In previous studies, pyrosequencing, mini-sequencing, real-time PCR, invader assays and other techniques have been used to detect CNVs. However, the higher the copy number in a genome, the more difficult it is to resolve the copies, so a more accurate method for measuring CNVs and assigning genotype is needed.</p> <p>Results</p> <p>PCR followed by a quantitative oligonucleotide ligation assay (qOLA) was developed for quantifying CNVs. The accuracy and precision of the assay were evaluated for porcine <it>KIT</it>, which was selected as a model locus. Overall, the root mean squares of bias and standard deviation of qOLA were 2.09 and 0.45, respectively. These values are less than half of those in the published pyrosequencing assay for analyzing CNV in porcine <it>KIT</it>. Using a combined method of qOLA and another pyrosequencing for quantitative analysis of <it>KIT </it>copies with spliced forms, we confirmed the segregation of <it>KIT </it>alleles in 145 F₁animals with pedigree information and verified the correct assignment of genotypes. In a diagnostic test on 100 randomly sampled commercial pigs, there was perfect agreement between the genotypes obtained by grouping observations on a scatter plot and by clustering using the nearest centroid sorting method implemented in PROC FASTCLUS of the SAS package. In a test on 159 Large White pigs, there were only two discrepancies between genotypes assigned by the two clustering methods (98.7% agreement), confirming that the quantitative ligation assay established here makes genotyping possible through the accurate measurement of high <it>KIT </it>copy numbers (>4 per diploid genome). Moreover, the assay is sensitive enough for use on DNA from hair follicles, indicating that DNA from various sources could be used.</p> <p>Conclusion</p> <p>We have established a high resolution quantification method using an oligonucleotide ligation assay to measure CNVs, and verified the reliability of genotype assignment for random animal samples using the nearest centroid sorting method. This new method will make it more practical to determine <it>KIT </it>CNV and to genotype the complicated <it>Dominant White/KIT </it>locus in pigs. This procedure could have wide applications for studying gene or segment CNVs in other species.</p

Familial Creutzfeldt-Jakob Disease with V180I Mutation

Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 per 1000,000 per year typically characterized by rapidly progressive dementia, ataxia, myoclonus and behavioral changes. Genetic prion diseases, which develop due to a mutations in the prion protein gene (PRNP), account for an estimated 10 to 15% of all CJD cases. We report a 75-yr-old woman with familial CJD carrying a V180I mutation which features late onset, slow progression, no periodic sharp wave complexes on electroencephalography, and extensive cortical ribboning with spared the cerebellum and the medial occipital lobes posterior to the parieto-occipital sulcus on MRI. To our knowledge, this is the first documented case of a point mutation at codon 180 in South Korea

Prognostic significance of lymph node yield on oncologic outcomes according to tumor response after preoperative chemoradiotherapy in rectal cancer patients

Purpose This study aimed to evaluate the predictive value of lymph node yield (LNY) for survival outcomes according to tumor response after preoperative chemoradiotherapy (PCRT) in patients with rectal cancer. Methods This study was a retrospective study conducted in a tertiary center. A total of 1,240 patients with clinical stage II or III rectal cancer who underwent curative resection after PCRT between 2007 and 2016 were included. Patients were categorized into the good response group (tumor regression grade [TRG], 0–1) or poor response group (TRG, 2–3). Propensity score matching was performed for age, sex, and pathologic stage between LNY of ≥12 and LNY of <12 within tumor response group. The primary outcome was 5-year disease-free survival (DFS) and overall survival (OS). Results LNY and positive lymph nodes were inversely correlated with TRG. In good responders, 5-year DFS and 5-year OS of patients with LNY of <12 were better than those with LNY of ≥12, but there was no statistical significance. In poor responders, the LNY of <12 group had worse survival outcomes than the LNY of ≥12 group, but there was also no statistical significance. LNY of ≥12 was not associated with DFS and OS in multivariate analysis. Conclusion LNY of <12 showed contrasting outcomes between the good and poor responders in 5-year DFS and OS. LNY of 12 may not imply adequate oncologic surgery or proper staging in rectal cancer patients treated by PCRT. Furthermore, a decrease in LNY should be comprehended differently according to tumor response

A Case of a Subepidermal Calcified Nodule on the Sole without Trauma

Subepidermal calcified nodule is an uncommon form of calcinosis cutis, which most commonly occurs in children. It usually presents as an asymptomatic, solitary verrucous nodule on the head and neck region, but occasionally as multiple lesions. Serum calcium and phosphorus levels are usually normal. Histopathology shows well-formed homogeneous eosinophilic material and granules in the upper dermis. Material in the dermis stained with von Kossa was positive. We report on an unusual case of a subepidermal calcified nodule occurring on the sole. A 21-month-old male presented with an oval-shaped, whitish, hard nodule measuring 5×5 mm on the left sole, without any previous history of trauma