The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease. (AU)

The role of microRNAs in the modulation of cancer-associated fibroblasts activity during pancreatic cancer pathogenesis.

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest of the common cancers. A major hallmark of PDAC is an abundant and dense fibrotic stroma, the result of a disproportionate deposition of extracellular matrix (ECM) proteins. Cancer-associated fibroblasts (CAFs) are the main mediators of PDAC desmoplasia. CAFs represent a heterogenous group of activated fibroblasts with different origins and activation mechanisms. microRNAs (miRNAs) are small non-coding RNAs with critical activity during tumour development and resistance to chemotherapy. Increasing evidence has revealed that miRNAs play a relevant role in the differentiation of normal fibroblasts into CAFs in PDAC. In this review, we discuss recent findings on the role of miRNAs in the activation of CAFs during the progression of PDAC and its response to therapy, as well as the potential role that PDAC-derived exosomal miRNAs may play in the activation of hepatic stellate cells (HSCs) and formation of liver metastasis. Since targeting of CAF activation may be a viable strategy for PDAC therapy, and miRNAs have emerged as potential therapeutic targets, understanding the biology underpinning miRNA-mediated tumour cell-CAF interactions is an important component in guiding rational approaches to treating this deadly disease.

Native pulmonary valve endocarditis requiring pulmonary valve replacement in adulthood: a case series.

Native pulmonary valve endocarditis is a rare phenomenon as native valve endocarditis tends to typically affect the left sided heart valves. However, the right-sided heart valves can be affected in patients with a history of intravenous drug use, whereby the tricuspid valve is most commonly affected. We present two cases who were diagnosed with native pulmonary valve endocarditis in the absence of congenital heart disease. In the first case, the native pulmonary valve endocarditis was probably a derivative of compounding factors of an enlarged underlying pulmonary artery and staphylococcal bacteraemia. In the second case, a common causal organism of native valve endocarditis following dental treatment and the resultant echocardiography findings was of significant interest. In summary, native pulmonary valve endocarditis is relatively rare complication in the adult population, especially in the absence of congenital heart disease.

Off-pump external pericardial patch repair for post-infarct left ventricular free wall rupture: a case series.

We describe an off-pump surgical approach to this challenging condition supported by our results from a case series, which would add to existing literature in the management of this life-threatening complication. We identified seven patients who underwent surgical intervention for left ventricular (LV) free wall rupture at our institution. They were all diagnosed to have cardiac tamponade secondary to free wall rupture of the LV in the presence of acute myocardial infarction. The surgical technique comprised of utilizing an external pericardial patch which was secured using surgical biological glues (fibrin-based sealants or gelatin hydrogels). The 30-day mortality, 1-year survival and 2-year survival were 57, 42 and 42%, respectively. Advanced age, female gender and use of cardiopulmonary bypass were characteristics that were not significantly associated with survival. We advocate the use of an off-pump external pericardial patch repair strategy as a 'bridge to recovery' in this extremely high-risk group of patients.

Progress in Arabidopsis genome sequencing and functional genomics.

Arabidopsis thaliana has a relatively small genome of approximately 130 Mb containing about 10% repetitive DNA. Genome sequencing studies reveal a gene-rich genome, predicted to contain approximately 25000 genes spaced on average every 4.5 kb. Between 10 to 20% of the predicted genes occur as clusters of related genes, indicating that local sequence duplication and subsequent divergence generates a significant proportion of gene families. In addition to gene families, repetitive sequences comprise individual and small clusters of two to three retroelements and other classes of smaller repeats. The clustering of highly repetitive elements is a striking feature of the A. thaliana genome emerging from sequence and other analyses.

Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana.

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Mebeverine decreases mass movements and stool frequency in lactulose-induced diarrhoea.

BACKGROUND: In spite of its frequent use in the treatment of irritable bowel disease little is known about mebeverine's mode of action in man. AIM: To examine mebeverine's effect on transit though the gut during lactulose-induced diarrhoea. METHODS: Nine healthy volunteers undertook a two-way randomized crossover study. Diarrhoea was induced using lactulose pre-treatment (20 m t.d.s., 4 days) and subjects received either mebeverine (135 mg t.d.s.) or no treatment. Transit of two enteric-coated capsules containing radiolabelled 8.4 mm tablets and 180-250 microM ion exchange resin were followed using gamma scintigraphy. Stool frequency and symptoms were assessed by diary cards. RESULTS: Mebeverine reduced mean daily stool frequency associated with lactulose ingestion from a median of 2.25 (interquartile range (IQR) 1.75-2.75) to 1.5 (IQR 1.25-2.25) movements. Mebeverine significantly reduced the number of mass movements observed in the colon during the 11 h of the study from 2 (2-2) to 1 (1-2), and the number of retrograde movements from 1 (0-2) to 0 (0-0) (P < 0.05). Mebeverine did not significantly alter the gastric emptying rate of the intact capsule (2.9 (1.9-3.2) to 2.8 (2.6-4.0) h) however it induced a small but significant acceleration in small intestinal transit of the capsule (1.6 (0.8-2.0) h to 1.0 (0.52-1.32) h, P=0.02). CONCLUSION: Mebeverine reduces the diarrhoeal effect of lactulose by decreasing the mass movements induced in the ascending colon. This effect may contribute to its clinical effect in irritable bowel syndrome.

Analysis of 1.9 Mb of contiguous sequence from chromosome 4 of Arabidopsis thaliana.

The plant Arabidopsis thaliana (Arabidopsis) has become an important model species for the study of many aspects of plant biology. The relatively small size of the nuclear genome and the availability of extensive physical maps of the five chromosomes provide a feasible basis for initiating sequencing of the five chromosomes. The YAC (yeast artificial chromosome)-based physical map of chromosome 4 was used to construct a sequence-ready map of cosmid and BAC (bacterial artificial chromosome) clones covering a 1.9-megabase (Mb) contiguous region, and the sequence of this region is reported here. Analysis of the sequence revealed an average gene density of one gene every 4.8 kilobases (kb), and 54% of the predicted genes had significant similarity to known genes. Other interesting features were found, such as the sequence of a disease-resistance gene locus, the distribution of retroelements, the frequent occurrence of clustered gene families, and the sequence of several classes of genes not previously encountered in plants.

Left ventricular false aneurysm after previous repair of acquired ventricular septal defect.

We report a novel case of a 69-year-old woman who was treated surgically for a postinfarction inferior ventricular septal defect and presented 3 years postoperatively with a large left ventricular false aneurysm. This was successfully repaired.

Oesophageal epiphrenic diverticulum: an unusual presentation and review.

Epiphrenic pulsion diverticula are rare and often asymptomatic. We describe a case presenting in an unusual fashion, and review the controversy over the management of this condition with regard to the requirement for myotomy and antireflux surgery. We believe that both procedures are necessary, but believe that both procedures are necessary, but optimal management strategies are unlikely to be resolved as the rarity of the condition precludes largescale prospective studies.

Adult congenital lobar emphysema in pregnancy.

A young woman presented with left sided chest pain. Chest radiography revealed a hyperexpanded left upper lobe and the rare diagnosis of congenital lobar emphysema was made. She was then found to be pregnant. Thoracotomy and left upper lobectomy were performed during the pregnancy without adverse effects to the mother or fetus. The implications of pregnancy on the surgical management of this rare condition are discussed.

Surgical presentations of Ehlers-Danlos syndrome type IV. A case report.

The case of a 28 year old man with Ehlers-Danlos syndrome (EDS) type IV is presented. He had the typical facies of this disorder, thin skin with atrophic scars and bruised easily. He suffered with congenital clubbed feet, heavy blood loss and poor wound healing following a traumatic compound fracture of the right leg, recurrent spontaneous pneumothoraces for which a pleurectomy was performed, two episodes of vascular rupture following minor trauma, one managed conservatively and the other surgically, and one episode of massive spontaneous vascular rupture which was fatal. In this report we highlight the surgical nature of the presenting complications of EDS type IV and demonstrate the hazards of surgical management. We conclude that, when possible, conservative management is preferable.

Spontaneous rupture of a congenital diaphragmatic eventration.

A 51-year-old man presented as an emergency with acute intestinal obstruction following herniation of abdominal contents into the left hemithorax through a spontaneous rupture of his eventrated left hemidiaphragm. He underwent a left thoracotomy with reduction of the herniated abdominal contents, repair of the diaphragmatic rupture and plication of the diaphragm. He made an uneventful recovery and remains asymptomatic. This is the first reported case of spontaneous rupture of an eventration of the diaphragm.

Anions, membrane resistance and ventricular fibrillation.

Clinical success in prevention of sudden cardiac death has been poor. New approaches to prevention of ventricular fibrillation (VF), one of the main causes of sudden cardiac death, are clearly needed. In the present article we have reviewed some of our own data which support the notion that VF may be prevented by manipulation of chloride homeostasis. Our studies have revealed a novel approach to VF suppression via alteration of sarcolemmal membrane resistance.

Kaufman's theory of shame and identity in treating childhood sexual abuse in adults.

The competent nurse/therapist treats shame of the adult survivor of childhood sexual abuse. Shame must be identified, validated, and treated. Kaufman's Developmental Theory of Shame and Identity is easily applied to post-sexual-abuse phenomenon. Treatment principles can be incorporated in both individual and group therapy. Nurse/therapists are encouraged to further explore the role of shame in the psychopathology of the adult survivor of childhood sexual abuse.

Anion manipulation, a novel antiarrhythmic approach: mechanism of action.

We recently reported that modulation of anion homeostasis by substitution of extracellular chloride by nitrate prevents ischaemia- and reperfusion-induced ventricular fibrillation (VF) in rat and rabbit in vitro by an unknown mechanism independent of haemodynamic changes but related to widening of QT interval (Ridley and Curtis 1991). In the present study we have examined three possible explanations for the mechanism: modification of membrane anion permeability, alteration of cyclic nucleotide homeostasis and alteration of intracellular pH. In isolated Langerdorff-perfused rat heart (n = 12/group), substitution of chloride in modified Krebs perfusion solution by anion surrogates (methylsulphate, bromide, nitrate or iodide) inhibited left regional ischaemia- and reperfusion-induced arrhythmias only when the membrane permeability of the surrogate was greater than that of chloride (e.g., nitrate, bromide, iodide); the least permeant anion, methylsulphate, was proarrhythmic during ischaemia. Rank order of arrhythmia susceptibility correlated with the relative permeability of each anion, with near abolition of both ischaemia- and reperfusion-induced VF (P < 0.05) by the most permeant anions (iodide and nitrate). Arrhythmia suppression occurring in the iodide and nitrate groups was accompanied by significant widening of QT interval at 90% repolarization, with effects substantially more marked during ischaemia than before ischaemia. In separate studies using the same model we determined cardiac cyclic (c) AMP and cGMP content and their molar ratios by radioimmunoassay of biopsies before, during and after ischaemia. There was no meaningful relation between cyclic nucleotide content and rank order of arrhythmia susceptibility ruling out changes in the former as a contributory mechanism to the latter. In further studies we measured intracellular pH in the isolated perfused rat heart by phosphorus NMR spectroscopy. Nitrate caused a slight intracellular acidosis which was exacerbated when hearts were made globally ischaemic, indicating that its antiarrhythmic activity was not a consequence of alkalinisation (e.g., via inhibition of chloride-bicarbonate exchange). To test for inherent adverse effects on cardiac contractile function we analysed Starling curves in isolated rat hearts perfused under conditions equivalent to those used for arrhythmia studies. There was no relationship between perfusion anion composition and systolic (developed pressure at constant intraventricular volume, and pressure-volume slope) or diastolic function (end-diastolic pressure at constant intraventricular volume). In conclusion, alteration of membrane permeability is a mechanism which may be sufficient to explain modulation of arrhythmias by manipulation of extracellular anion content, appears to be devoid of deleterious effects on contractile function, and may represent a focus for future antiarrhythmic drug development.

Heterotopic heart transplantation and recipient heart operation in ischemic heart disease.

The role of heterotopic heart transplantation in coronary heart disease has not been defined. Between 1983 and 1988, 28 patients with end-stage ischemic heart disease were managed by heterotopic heart transplantation and adjunctive operation on the recipient heart: coronary artery bypass grafts and aneurysmectomy, 20; coronary artery bypass grafts, 5; and aneurysmectomy, 3. Indications were feasibility of operative procedures to the recipient heart and small donor size (61% of the donors were less than 15 years). The 1-year and 5-year actuarial survival was 79% and 63%. Of the 22 patients who survived to 2-year follow-up, all of whom had been severely limited (New York Heart Association grade III/IV) preoperatively, 20 were in grades I or II at 2-year follow-up (p less than 0.001). In 14 of 22 patients (64%), the recipient heart augmented the donor cardiac output substantially, and in 4 the recipient heart supported the patient when the donor heart failed to eject. In conclusion, this series demonstrates the efficacy of heterotopic transplantation combined with operation to the recipient heart in the management of patients with end-stage ischemic heart disease.