We sought to determine whether PI3K pathway mutation or activation state and rapamycin-induced feedback-loop activation of Akt is associated with rapamycin sensitivity or resistance.
Cancer cell lines were tested for rapamycin-sensitivity, Akt phosphorylation and mTOR target inhibition. Mice injected with breast or neuroendocrine cancer cells and patients with neuroendocrine tumor (NET) were treated with rapalogs, and Akt phosphorylation was assessed.
31 cell lines were rapamycin-sensitive (RS) and 12 were relatively rapamycin-resistant (RR; IC50>100 nM). Cells with PIK3CA and/or PTEN mutations were more likely to be RS (p=0.0123). Akt phosphorylation (S473 and T308) was significantly higher in RS cells (p<0.0001). Rapamycin led to a significantly greater pathway inhibition and greater increase in p-Akt T308 (p<0.0001) and p-Akt S473 (p=0.0009) in RS cells. Rapamycin and everolimus significantly increased Akt phosphorylation but inhibited growth in an in vivo NET model (BON). In patients with NETs treated with everolimus and octreotide, progression-free survival correlated with p-Akt T308 in pretreatment (R=0.4762, p=0.0533) and on-treatment tumor biopsies (R=0.6041, p=0.0102). Patients who had a documented partial response were more likely to have an increase in p-Akt T308 with treatment compared to non-responders (p=0.0146).
PIK3CA/PTEN genomic aberrations and high p-Akt levels are associated with rapamycin sensitivity in vitro. Rapamycin-mediated Akt activation is greater in RS cells, with a similar observation in patients with clinical responses on exploratory biomarker analysis; thus feedback-loop activation of Akt is not a marker of resistance but rather may function as an indicator of rapamycin activity.
Akt; mTOR; rapamycin sensitivity; RPPA; everolimus; pharmacodynamic markers
Acetylation of the tumor suppressor gene p53 at the carboxy-terminal lysine (Lys) residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis. Histone deacetylases (HDACs), a family of evolutionarily conserved enzymes, counterbalance the acetylation of lysine residues on histone and non-histone proteins. In this study, we demonstrate that green tea polyphenols (GTPs) and their major constituent, (−) epigallocatechin-3-gallate (EGCG), activate p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in LNCaP human prostate cancer cells. Treatment of cells with GTPs (2.5–10 µg/ml) and EGCG (5–20 µM) resulted in dose- and time-dependent inhibition of class I HDACs (HDAC1, 2, 3 and 8), albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with increased accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs, a function that is likely to be part of the mechanisms that control the physiological activity of p53.
prostate cancer; green tea polyphenols; epigallocatechin-3-gallate; p53 acetylation; histone deacetylases
Signal transducer and activator of transcription (Stat)-3 and nuclear factor-kappa B (NF-κB) are important signaling pathways constitutively activated during inflammation. We previously reported that high-fat diet (HFD) intake induces oxidative stress in the prostate through elevated expression of NADPH oxidase subunits causing NF-κB activation. We sought to determine whether Stat-3 is involved in the activation of NF-κB in the prostate as a result of HFD feeding, leading to inflammation.
C57BL/6 mice were either fed with regular diet (RD) or HFD for 4 and 8 weeks. Plasma cytokine levels were determined by multiplex analysis. Western blotting was performed to determine the expression of NF-κB, Stat-3, Akt, PDK1, PKCε and their phosphorylated forms along with pathologic evaluation of the prostate. Immunoprecipitation and electrophoretic mobility shift assay were conducted to study the association between Stat-3 and NF-κB.
C57BL/6 mice fed with HFD showed a significant increase in the plasma levels of IL-1β, IL-6, IL-17 and TNFα after 4 and 8 weeks of feeding, compared with RD controls. HFD feeding elevated the intraprostatic expression of IL-6 and caused activation of PKCε and Akt, the upstream kinase regulating Stat-3 and NF-κB. Nuclear extracts from the prostates of mice fed with HFD exhibited constitutively activated levels of Stat-3 and NF-κB/p65. Increased association between the activated forms of Stat-3 and NF-κB/p65 was observed in the nucleus as a result of HFD feeding, a finding that was accompanied by morphologic evidence of increased intraprostatic inflammation.
Our findings suggest that HFD activates Stat-3 and NF-κB/p65 in the prostate, and their interaction is associated with increased inflammation in the prostate.
inflammation; high-fat diet; prostate; Stat-3; NF-κB
Green tea polyphenols (GTPs) reactivate epigenetically silenced genes in cancer cells and trigger cell cycle arrest and apoptosis; however, the mechanisms whereby these effects occur are not well understood. We investigated the molecular mechanisms underlying the antiproliferative effects of GTP, which may be similar to those of histone deacetylase (HDAC) inhibitors. Exposure of human prostate cancer LNCaP cells (harboring wild-type p53) and PC-3 cells (lacking p53) with 10–80 μg/ml of GTP for 24 h resulted in dose-dependent inhibition of class I HDAC enzyme activity and its protein expression. GTP treatment causes an accumulation of acetylated histone H3 in total cellular chromatin, resulting in increased accessibility to bind with the promoter sequences of p21/waf1 and Bax, consistent with the effects elicited by an HDAC inhibitor, trichostatin A. GTP treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. Furthermore, treatment of cells with proteasome inhibitor, MG132 together with GTP prevented degradation of class I HDACs, compared with cells treated with GTP alone, indicating increased proteasomal degradation of class I HDACs by GTP. These alterations were consistent with G0–G1 phase cell cycle arrest and induction of apoptosis in both cell lines. Our findings provide new insight into the mechanisms of GTP action in human prostate cancer cells irrespective of their p53 status and suggest a novel approach to prevention and/or therapy of prostate cancer achieved via HDAC inhibition.
Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high.
The 2013 update of the World Society of Emergency Surgery (WSES) guidelines for the management of intra-abdominal infections contains evidence-based recommendations for management of patients with intra-abdominal infections.
Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition.
Despite advances in diagnosis, surgery, and antimicrobial therapy, mortality rates associated with complicated intra-abdominal infections remain exceedingly high. The World Society of Emergency Surgery (WSES) has designed the CIAOW study in order to describe the clinical, microbiological, and management-related profiles of both community- and healthcare-acquired complicated intra-abdominal infections in a worldwide context. The CIAOW study (Complicated Intra-Abdominal infection Observational Worldwide Study) is a multicenter observational study currently underway in 57 medical institutions worldwide. The study includes patients undergoing surgery or interventional drainage to address complicated intra-abdominal infections. This preliminary report includes all data from almost the first two months of the six-month study period. Patients who met inclusion criteria with either community-acquired or healthcare-associated complicated intra-abdominal infections (IAIs) were included in the study. 702 patients with a mean age of 49.2 years (range 18–98) were enrolled in the study. 272 patients (38.7%) were women and 430 (62.3%) were men. Among these patients, 615 (87.6%) were affected by community-acquired IAIs while the remaining 87 (12.4%) suffered from healthcare-associated infections. Generalized peritonitis was observed in 304 patients (43.3%), whereas localized peritonitis or abscesses was registered in 398 (57.7%) patients.
The overall mortality rate was 10.1% (71/702). The final results of the CIAOW Study will be published following the conclusion of the study period in March 2013.
Inactivation of the tumor suppressor gene p53 is commonly observed in human prostate cancer and is associated with therapeutic resistance. We have previously demonstrated that green tea polyphenols (GTP) induce apoptosis in prostate cancer cells irrespective of p53 status. However, the molecular mechanisms underlying these observations remain elusive. Here we investigated the mechanisms of GTP-induced apoptosis in human prostate cancer LNCaP cells stably-transfected with short hairpin-RNA against p53 (LNCaPshp53) and control vector (LNCaPshV). GTP treatment induced p53 stabilization and activation of downstream targets p21/waf1 and Bax in a dose-dependent manner specifically in LNCaPshV cells. However, GTP-induced FAS upregulation through activation of c-jun-N-terminal kinase resulted in FADD phosphorylation, caspase-8 activation and truncation of BID, leading to apoptosis in both LNCaPshV and LNCaPshp53 cells. In parallel, treatment of cells with GTP resulted in inhibition of survival pathway, mediated by Akt deactivation and loss of BAD phosphorylation more prominently in LNCaPshp53 cells. These distinct routes of cell death converged to a common pathway, leading to loss of mitochondrial transmembrane potential, cytochrome c release and activation of terminal caspases, resulting in PARP-cleavage. GTP-induced apoptosis was attenuated with JNK inhibitor, SP600125 in both cell lines; whereas PI3K-Akt inhibitor, LY294002 resulted in increased cell death prominently in LNCaPshp53 cells, establishing the role of two distinct pathways of GTP-mediated apoptosis. Furthermore, GTP exposure resulted in inhibition of class I HDAC protein, accumulation of acetylated histone-H3 in total cellular chromatin, resulting in increased accessibility of transcription factors to bind with the promoter sequences of p21/waf1 and Bax, regardless of the p53 status of cells, consistent with effects elicited by an HDAC inhibitor, trichostatin A. These results demonstrate that GTP induces prostate cancer cell death by two distinct mechanisms regardless of p53 status, thus identifying specific well-defined molecular mechanisms that may be targeted by chemopreventive and/or therapeutic strategies.
Introduction. Donor workup in renal transplantation is extensive. Despite this, chyle leakage following donor nephrectomy, a rare complication, has been reported in the literature. We encountered two cases of chyle leak in kidney donors in our series of open donor nephrectomies. Summary of Cases. After complete workup, standard open retroperitoneal donor nephrectomy with drain placement was performed in 684 living renal donors. We encountered chyle leak in two cases. The first case was a 33-year-old female who underwent an otherwise uneventful left donor nephrectomy but continued to have high drain output (upto 300–400 mL/24 hrs) in the postoperative period. The drain fluid was milky, raising the suspicion of chyle which was confirmed on biochemical analysis. The second case was a 42-year-old female with a similar case history. Both were managed conservatively with low-fat diet. The leak subsided spontaneously in three weeks and one week in the first and second patients, respectively. The drain was removed, and the patients remained symptom-free on followup. Conclusions. Both of our cases of chyle leak following open donor nephrectomy were managed successfully with conservative management. The management options and the experience of other centers are reviewed and discussed.
Introduction. Tophaceous gout of the patella is rare and may masquerade as a tumour or tumour-like condition. Cases. We report two patients with gout involving the patella, one complicated by a pathological fracture and the other occurring in a bipartite patella in a young adult. Discussion. Typical imaging appearances and measurement of serum urate will usually confirm the diagnosis but, occasionally, the serum urate level may be normal in active gout and in such cases, a biopsy will be required. Conclusion. Gout of the patella may masquerade as a tumour or tumour-like condition and it is important to consider gout in the differential diagnosis.
Female mice lacking DEF6 and SWAP70 develop a lupus-like syndrome through dysregulation of IRF4 in activated B cells and plasma cells.
Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T–B cell interactions.
Despite advances in controlled drug delivery, reliable methods for activatable, high-resolution control of drug release are needed. We hypothesized that the photothermal effect mediated by a near-infrared (NIR) laser and hollow gold nanospheres (HAuNS) could modulate the release of anticancer agents. We tested this hypothesis by developing biodegradable and biocompatible microspheres (1~15 µm) containing the antitumor drug paclitaxel (PTX) and HAuNS (~35 nm in diameter) displaying surface plasmon absorbance in the near-infrared (NIR) region. HAuNS-containing microspheres exhibited an NIR light-induced thermal effect similar to that of plain HAuNS. Rapid, repetitive PTX release from the PTX/HAuNS-containing microspheres was observed when microspheres were irradiated with NIR light (808 nm), whereas PTX release became insignificant when NIR light was switched off. The release of PTX from the microspheres could be readily controlled by NIR laser output power, duration of laser irradiation, treatment frequency, and the concentration of HAuNS embedded inside the microspheres. In vitro, cancer cells incubated with PTX/HAuNS-loaded microspheres and irradiated with NIR light displayed significantly greater cytotoxic effects than cells incubated with the microspheres alone or cells irradiated with NIR light alone, owing to NIR light-triggered drug release. Treatment of human U87 gliomas and MDA-MB-231 mammary tumor xenografts in nude mice with intratumoral injection of PTX/HAuNS-loaded microspheres followed by NIR irradiation resulted in significant tumor growth delay compared to tumors treated with HAuNS-loaded microspheres (no PTX) and NIR irradiation or with PTX/HAuNS-loaded microspheres alone. Our data support the feasibility of a therapeutic approach in which NIR light is used for simultaneous modulation of drug release and induction of photothermal cell killing.
Near-infrared light; Photothermal effect; Hollow gold nanospheres; Microspheres; Paclitaxel; Triggered drug release
The absence of user-friendly systems for reporting complications is a major barrier to improving quality assurance (QA) programs in interventional radiology (IR) services. We describe the implementation of a QA application that is completely integrated with the radiology dictation system. We implemented an IR QA process as a module within the electronic medical record and radiologist dictation system applications used at our institution. After a radiologist completes a dictation, he or she must select from a drop-down list of complications before proceeding to the next case. Delayed QA events can be entered using the same applications. All complication entries are sent to a database, which is queried to run reports. During the study period, all the 20,034 interventional procedures were entered in the QA database, 1,144 complications were reported, 110 (9.6%) of which were classified as major. Although majority of the complications (996) were entered at the time of dictation, 148 complications (12.9%) were entered afterwards. All major complications were referred to the IR peer review committee, and 30 of these were discussed in the morbidity and mortality meetings. We studied post-lung-biopsy pneumothorax and chest tube rates and initiated a quality improvement process based on the results.The integration of the IR QA reporting system into the workflow process and the mandatory requirements for completion has the potential to minimize the work effort required to enter complication data, and improve participation in the QA process.
Interventional radiology; quality assurance; complications; data collection; workflow
Phenytoin is a commonly used antiepileptic medication because of its easy accessibility as well as affordability. However, scientific literature shows various types of side effects of phenytoin. We report a patient who was showing toxicity symptoms in the form of mood, behavior and cognitive symptoms along with scholastic problems and personality change on long term treatment with phenytoin. The patient's serum phenytoin was found to be quite high (>32.8 ng/ml).The symptoms were attributed to phenytoin toxicity which responded within twelve weeks by reducing the dose of phenytoin (with resultant fall in levels of serum phenytoin) and the addition of folic acid. While the mood and behavior symptoms recovered early, the cognitive symptoms responded slowly showing 80% -90 % improvement over a period of fifteen weeks.
Antiepileptic; cognitive; phenytoin; scholastic; toxicity
Perianal extra-mammary Paget's disease is a rare skin disorder of unknown aetiology, which is frequently associated with malignancy. This case report draws attention to this rare condition and comments upon its diagnosis and treatment.
PRESENTATION OF CASE
A 64-year-old otherwise fit man, presented to us in 2006 with one-year-long history of perianal irritation. On examination there was an erythematous discoid skin lesion in the right perianal area. The lesion was excised with wide margins and the defect closed with a local transposition flap. Histology confirmed extra-mammary Paget's disease (EMPD) with a focus of invasion showing a well-differentiated mucinous adenocarcinoma. Adjuvant therapy was not advised. On follow-up in 2011, a small irregular skin lesion, well away from the previous excision site was noted on the left perianal area. Biopsies from this lesion confirmed EMPD with no focus of invasion. Once again wide local excision with closure using local transposition flap was undertaken. Long term follow up has been advised.
The optimal treatment for Perianal Paget's disease (PPD) remains controversial. Surgery is the commonest modality used with wide local excision being the treatment of choice for resectable disease. We report herein a short review of various therapies reported so far in the management of this rare disorder.
A thorough initial evaluation and long-term follow-up is essential to identify recurrence and the development of other related malignancies.
Extramammary Paget's disease; Perianal Paget's disease
Kartagener's syndrome is a very rare congenital malformation comprising of a classic triad of sinusitis, situs inversus and bronchiectasis. Primary ciliary dyskinesia is a genetic disorder with manifestations present from early life and this distinguishes it from acquired mucociliary disorders. Approximately one half of patients with primary ciliary dyskinesia have situs inversus and, thus are having Kartagener syndrome. We present a case of 12 year old boy with sinusitis, situs inversus and bronchiectasis. The correct diagnosis of this rare congenital autosomal recessive disorder in early life is important in the overall prognosis of the syndrome, as many of the complications can be prevented if timely management is instituted, as was done in this in this case.
Bronchiectasis; primary ciliary dyskinesia; Kartagener's syndrome; sinusitis; situs inversus
This randomized clinical trial was conducted to compare a fistulectomy and a fistulotomy with marsupialization in the management of a simple anal fistula.
Forty patients with simple anal fistula were randomized into two groups. Fistulous tracts were managed by using a fistulectomy (group A) while a fistulotomy with marsupialization was performed in group B. The primary outcome measure was wound healing time while secondary outcome measures were operating time, postoperative wound size, postoperative pain, wound infection, anal incontinence, recurrence and patient satisfaction.
Postoperative wounds in group B healed earlier in comparison to group A wounds (4.85 ± 1.39 weeks vs. 6.75 ± 1.83 weeks, P = 0.035). No significant differences existed between the operating times (28.00 ± 6.35 minutes vs. 28.20 ± 6.57 minutes, P = 0.925) and visual analogue scale scores for postoperative pain on the first postoperative day (4.05 ± 1.47 vs. 4.50 ± 1.32, P = 0.221) for the two groups. Postoperative wounds were larger in group A than in group B (2.07 ± 0.1.90 cm2 vs. 1.23 ± 0.87 cm2), however this difference did not reach statistical significance (P = 0.192). Wound discharge was observed for a significantly longer duration in group A than in group B (4.10 ± 1.91 weeks vs. 2.75 ± 1.71 weeks, P = 0.035). There were no differences in social and sexual activities after surgery between the patients of the two groups. No patient developed anal incontinence or recurrence during the follow-up period of twelve weeks.
In comparison to a fistulectomy, a fistulotomy with marsupialization results in faster healing and a shorter duration of wound discharge without increasing the operating time.
Fistulectomy; Fistulotomy; Anal fistula
Tea is the second most consumed beverage in the world reported to have multiple health benefits. Preventive and therapeutic benefits of tea polyphenols include enhanced general well being and anti-neoplastic effects. The pharmacologic action of tea is often attributed to various catechins present therein. Experiments conducted in cancer cell lines and animal models demonstrate that tea polyphenols protect against cellular damage caused by oxidative stress and altered immunity. Tea polyphenols modify various metabolic and signaling pathways in the regulation of proliferation, apoptosis, angiogenesis, and metastasis and therefore restrict clonal expansion of cancer cells. Tea polyphenols have been shown to reactivate tumor suppressors, block the unlimited replicative potential of cancer cells, and physically bind to nucleic acids involved in epigenetic alterations of gene regulation. Remarkable interest in green tea as a potential chemopreventive agent has been generated since recent epigenetic data showed that tea polyphenols have the potential to reverse epigenetic modifications which might otherwise be carcinogenic. Like green tea, black tea may also possess chemopreventive and chemotherapeutic potential; however, there is still not enough evidence available to make any conclusive statements. Here we present a brief description of tea polyphenols and discuss the findings of various in vitro and in vivo studies of the anticancer effects of tea polyphenols. Detailed discussion of various studies related to epigenetic changes caused by tea polyphenols leading to prevention of oncogenesis or cancer progression is included. Finally, we discuss on the scope and development of tea polyphenols in cancer prevention and therapy.
Apoptosis; Angiogenesis; Cancer; Epigenetics; Green tea; Tea catechins; Metastasis
Aberrant production of IL-21 by T cells is critical for the development of type 1 diabetes (T1D) in NOD mice. The pathogenic effects of IL-21 are partly due to its ability to promote the generation of TH-17 cells. Interferon Regulatory Factor (IRF4) is a crucial regulator of IL-17 and IL-21 production. We recently found that the serine-threonine kinase ROCK2 phosphorylates IRF4 and regulates its ability to control IL-17 and IL-21 production. Here we show that NOD T cells aberrantly activate ROCK2. We furthermore demonstrate that ROCK inhibition corrects the abnormal IRF4 function in NOD T cells and diminishes their production of IL-17 and IL-21. Importantly, administration of a ROCK inhibitor to NOD mice protects against diabetes development. These studies thus support the idea that ROCK2 is inappropriately activated in NOD T cells and that ROCK kinases could represent important therapeutic targets for the treatment of T1D.
Members of Streptomyces produce 70% of natural bioactive products. There is considerable amount of information available based
on polyphasic approach for classification of Streptomyces. However, this information based on phenotypic, genotypic and bioactive
component production profiles is crucial for pharmacological screening programmes. This is scattered across various journals,
books and other resources, many of which are not freely accessible. The designed database incorporates polyphasic typing
information using combinations of search options to aid in efficient screening of new isolates. This will help in the preliminary
categorization of appropriate groups. It is a free relational database compatible with existing operating systems. A cross platform
technology with XAMPP Web server has been used to develop, manage, and facilitate the user query effectively with database
support. Employment of PHP, a platform-independent scripting language, embedded in HTML and the database management
software MySQL will facilitate dynamic information storage and retrieval. The user-friendly, open and flexible freeware (PHP,
MySQL and Apache) is foreseen to reduce running and maintenance cost.
Streptomyces; PHP; MySQL; Literature; Molecular
Histones are abundant nuclear proteins that are essential for the packaging of eukaryotic DNA into chromosomes. Different histone variants, in combination with their modification ‘code’, control regulation of gene expression in diverse cellular processes. Several enzymes that catalyze the addition and removal of multiple histone modifications have been discovered in the past decade, enabling investigations of their role(s) in normal cellular processes and diverse pathological conditions. This sudden influx of data, however, has resulted in need of an updated knowledgebase that compiles, organizes and presents curated scientific information to the user in an easily accessible format. Here, we present HIstome, a browsable, manually curated, relational database that provides information about human histone proteins, their sites of modifications, variants and modifying enzymes. HIstome is a knowledgebase of 55 human histone proteins, 106 distinct sites of their post-translational modifications (PTMs) and 152 histone-modifying enzymes. Entries have been grouped into 5 types of histones, 8 types of post-translational modifications and 14 types of enzymes that catalyze addition and removal of these modifications. The resource will be useful for epigeneticists, pharmacologists and clinicians. HIstome: The Histone Infobase is available online at http://www.iiserpune.ac.in/∼coee/histome/ and http://www.actrec.gov.in/histome/.
Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) can provide unique data on the transmural extent of scar/viability. We assessed the prevalence of dysfunctional myocardium, including partial thickness scar, which could contribute to left ventricular contractile dysfunction in patients with heart failure and ischaemic heart disease who denied angina symptoms.
We invited patients with ischaemic heart disease and a left ventricular ejection fraction < 50% by echocardiography to have LGE CMR. Myocardial contractility and transmural extent of scar were assessed using a 17-segment model.
The median age of the 193 patients enrolled was 70 (interquartile range: 63-76) years and 167 (87%) were men. Of 3281 myocardial segments assessed, 1759 (54%) were dysfunctional, of which 581 (33%) showed no scar, 623 (35%) had scar affecting ≤50% of wall thickness and 555 (32%) had scar affecting > 50% of wall thickness. Of 1522 segments with normal contractile function, only 98 (6%) had evidence of scar on CMR. Overall, 182 (94%) patients had ≥1 and 107 (55%) patients had ≥5 segments with contractile dysfunction that had no scar or ≤50% transmural scar suggesting viability.
In this cohort of patients with left ventricular systolic dysfunction and ischaemic heart disease, about half of all segments had contractile dysfunction but only one third of these had > 50% of the wall thickness affected by scar, suggesting that most dysfunctional segments could improve in response to an appropriate intervention.
Heart failure; Myocardial infarction; Hibernation; Cardiovascular magnetic resonance imaging; Late gadolinium enhancement