Acute colonic pseudo-obstruction: a retrospective review of the surgical outcomes.

PURPOSE: Limited data exist regarding the surgical outcomes of acute colonic pseudo-obstruction (ACPO), commonly referred to as Ogilvie syndrome, in modern clinical practice. The prevailing belief is that surgery should be avoided due to previously reported high mortality rates. We aimed to describe the surgical results of ACPO treated within our institution. METHODS: Our prospectively maintained colorectal surgery registry was queried for patients diagnosed with ACPO, who underwent surgery between 2009 and 2022. Postoperative complications were graded according to Clavien-Dindo (CD) classification. The primary outcome was postoperative mortality. RESULTS: A total of 32 patients who underwent surgery for ACPO were identified. Overall, nonoperative therapy was initially administered to 21 patients (65.6%). The surgeries performed included total abdominal colectomy (15, 43.1%), ascending colectomy with end ileostomy (8, 25%), transverse colostomy (5, 15.6%), ileostomy and transverse colostomy (3, 9.4%), and Hartmann's operation (1, 3.1%). Severe postoperative complications (CD grade 3 or 4) occurred in five patients (15.6%). No recurrence of ACPO was observed and no patient required reoperation. The average postoperative length of stay was 14.5 days, 30-day mortality was 6.3% (n = 2), and 90-day mortality was 15.6% (n = 5) due to complications of underlying comorbidities. CONCLUSIONS: Surgical treatment was effective for patients with ACPO refractory to medical therapy or presenting with acute complications. Although postoperative complications were frequent, both the 30- and 90-day mortality rates were lower than previously documented in the literature. Further investigations are warranted to determine the optimal surgical strategy, which may involve total or segmental colectomy, or diversion alone without resection.

Surgery for young onset diverticulitis: is it curative?

PURPOSE: Previously considered a disease of old age, diverticular disease is increasingly prevalent in younger populations. Guidelines on surgical resection have shifted from recommending resection for all young onset patients to an individualized approach. Therefore, we aim to determine demographics and outcomes including radiographic and surgical recurrence rates in patients < 40 years old undergoing resection for diverticular disease. METHODS: A retrospective, single center study was performed. All patients ≤ 39 years undergoing operative intervention for left-sided diverticular disease between Jan 2010 and July 2017 were included. Recurrence was determined by individual review of imaging and operative reports. RESULTS: Overall, 147 (n = 107/72.8% male, mean age = 34.93 ± 4.12 years) patients were included. The majority were ASA 1 or 2 (n = 41/27.9% and n = 82/55.8%). The most common surgical indication was uncomplicated diverticulitis (n = 77, 52.4%) followed by perforation (n = 26/17.7%). The majority (n = 108/73.5%) of cases were elective. Seventy-nine (57.3%) of all cases were performed laparoscopically. Primary anastomosis without diversion was the most common surgical outcome (n = 108/73.5%). Median length of stay was 5 (4, 7) days. There was no mortality. There were three (2.0%) intraoperative and 38 (25.9%) postoperative complications. The most common complication was anastomotic leak (n = 6/4.1%). The majority (n = 5) of leaks occurred after elective surgery. Two neoplastic lesions (1.3% of cohort) were found (1 adenoma with low-grade dysplasia/1 polyp cancer). Over a mean follow-up of 96 (74, 123) months, only 2 (1.3%) patients experienced a surgical or radiological recurrence. CONCLUSION: Both neoplasia and recurrence after resection for diverticular disease in young onset patients are rare. Leaks after primary anastomosis even in the elective setting warrant careful consideration of a defunctioning ileostomy.

Low incidence of occult colorectal carcinoma in a cohort of 150 consecutive patients with diverticular strictures.

BACKGROUND: The symptoms of stricturing diverticulitis can overlap with those of colorectal cancer. Additionally, the stricture itself may mask a "hidden" colorectal cancer. We aimed to describe the demographics, operative details and outcomes, including occult colorectal cancer, in a cohort of consecutive resections for presumed diverticular strictures. METHODS: In this single-center, retrospective cohort study, all patients undergoing resection for a presumed diverticular stricture between January 2010 and December 2015 were included. Preoperative imaging and colonoscopies were individually reviewed. Only patients with radiographically, endoscopically and/or intraoperatively benign-appearing strictures were included. RESULTS: One hundred fifty patients (72.7% female, mean age = 70.4 ± 11.8 years, 62.7% elective) were included. Only 34 (22.7%) had a complete preoperative colonoscopy. In 95 (63.6% of cohort) patients, the stricture was non-traversable colonoscopically. Overall, 47 (31.3%) patients did not have complete preoperative imaging or a colonoscopy. In total, 53.3% were open procedures and 62% had non-diverted primary anastomosis. Eleven (14.7%) underwent resection of adjacent organs (5 appendixes/5 right colons/7 fallopian tubes ± ovaries/3 small bowel resections/2 partial cystectomies/1 spleen). The median length of stay was 7 (5, 12.5) days. Only 2 cancers (1.3% of patients) involving the stricture (1 invasive moderately differentiated sigmoid adenocarcinoma/1 lymphoma) were found. Three additional cancers were found in organs involved in the inflammatory process (20% of concomitantly resected organs, 1 ovarian carcinoma/1 leukemia in a lymph node/1 appendiceal tumor). CONCLUSION: Despite approximately one-third of the cohort not having undergone successful preoperative colonoscopy or imaging, the rate of neoplasia involving diverticular strictures was only 1.3%. A relatively high cancer rate was found in concomitantly resected organs involved in the stricturing process.

Outcomes After Colonic Self-Expanding Metal Stent Insertion Without Fluoroscopy: A Surgeon-Led 10-Year Experience.

INTRODUCTION: Colonic self-expanding metal stents (SEMS) can be used to relieve malignant and benign large bowel obstruction (LBO) as a bridge to surgery (BTS) and for palliation. Guidelines suggest the use of fluoroscopic guidance for deployment. This may be difficult to obtain after hours and in certain centers. We aimed to determine the outcomes of stenting under endoscopic guidance alone. METHODS: All patients who underwent SEMS insertion in our tertiary referral center between August 2010 and June 2021 were identified from a prospectively maintained database. Patient demographics (age/gender), disease characteristics (benign versus malignant/location/stage), stenting intent (BTS versus palliative), and outcomes (technical success/stoma/time from stenting to resection/death/study end) were analyzed. RESULTS: Fifty-three (n = 39, 73.6% male) patients underwent SEMS insertion. Indications included colorectal carcinoma (n = 48, 90.6%), diverticular stricture (n = 3), and gynecological malignancy (n = 2). In five (9.4%) patients (four BTS and one palliative), SEMSs deployment was not completed because of the inability to pass the guidewire. All underwent emergency surgery. In the BTS cohort (n = 29, median 70.4 [range 40.3-91.8] years), 10 patients underwent neoadjuvant chemoradiotherapy. The permanent stoma rate was 20.7% (n = 6). There was no 30- or 90-d mortality. In the palliative cohort (n = 24, median age 77.1 [range 54.4-91.9]), 16 (66.7%) were deceased at the study end. The median time from stenting to death was 5.2 (2.3-7.9) months. CONCLUSIONS: SEMS placed under endoscopic visualization alone, palliatively and as a BTS, had acceptable stoma, morbidity, and mortality rates. These results show that SEMS insertion can be safely performed without fluoroscopy.

Poor patient awareness of peripheral arterial disease, it is time to optimize the clinical visit.

INTRODUCTION: Peripheral arterial disease (PAD) is a growing public health burden. The development and progression of PAD is influenced by vascular risk factor management and lifestyle changes. However, public awareness of PAD is low compared with other conditions such as heart disease and stroke, which have been the subject of widespread public health campaigns. This study aimed to determine current levels of PAD awareness among hospital patients. METHODS: This cross-sectional, tertiary hospital-based, descriptive study was conducted over 6 months in 2019. Two investigators administered the survey in face-to-face interviews to patients attending 3 different hospital-based settings including vascular clinics (VC), cardiology clinics (CVC), and Emergency Department (ED). RESULTS: A total of 150 patients were interviewed. Participants demonstrated low overall awareness of vascular disease (32% PAD and 21% AAA) compared to cardiovascular disease including stroke (71%) and myocardial infarction (63%). Awareness of PAD was higher in vascular patients (51%) compared to CVC and ED patients (p=<0.01). Of the total population, 77% and 71% identified the contributory role of smoking and limited exercise to the development of PAD respectively. VC patients were more informed of intermittent claudication (78%) and amputation (80%) (p < 0.01) compared to CVC and ED patients. CONCLUSION: In the global drive to reduce vascular morbidity, this study highlights the poor knowledge of PAD among the public. In addition, there is poor awareness about the incidence, risk factors and complications of PAD. These results highlight the need for accessible and easily understood information regarding PAD in both the clinic setting and public health campaigns.

The Association of Coloproctology of Great Britain and Ireland consensus guidelines in emergency colorectal surgery.

AIM: There is a requirement for an expansive and up to date review of the management of emergency colorectal conditions seen in adults. The primary objective is to provide detailed evidence-based guidelines for the target audience of general and colorectal surgeons who are responsible for an adult population and who practise in Great Britain and Ireland. METHODS: Surgeons who are elected members of the Association of Coloproctology of Great Britain and Ireland Emergency Surgery Subcommittee were invited to contribute various sections to the guidelines. They were directed to produce a pathology-based document using literature searches that were systematic, comprehensible, transparent and reproducible. Levels of evidence were graded. Each author was asked to provide a set of recommendations which were evidence-based and unambiguous. These recommendations were submitted to the whole guideline group and scored. They were then refined and submitted to a second vote. Only those that achieved >80% consensus at level 5 (strongly agree) or level 4 (agree) after two votes were included in the guidelines. RESULTS: All aspects of care (excluding abdominal trauma) for emergency colorectal conditions have been included along with 122 recommendations for management. CONCLUSION: These guidelines provide an up to date and evidence-based summary of the current surgical knowledge in the management of emergency colorectal conditions and should serve as practical text for clinicians managing colorectal conditions in the emergency setting.

A giant duodenal diverticulum causing Lemmel syndrome.

An 80-year-old female, with a known periampullary giant duodenal diverticulum, presented to the emergency department with general deterioration. While not clinically icteric, her laboratory investigations revealed an obstructive jaundice. MRCP demonstrated mild distension of the gallbladder with several calculi. There was intra- and extra-hepatic biliary dilatation to the level of the ampulla. A giant fluid and air filled periampullary duodenal diverticulum measuring ~8 cm in the long axis was noted. The CBD was dilated to the level of this diverticulum and the cause of the patient's biliary dilatation and obstruction. A rare pancreaticobiliary complication of duodenal diverticula is Lemmel syndrome. Lemmel syndrome is defined as an obstructive jaundice caused by a periampullary duodenal diverticulum compressing the intra-pancreatic portion of the common bile duct with resultant dilatation of the extra- and intra-hepatic bile ducts. Recognition of this condition is important, as delayed diagnosis can result in unnecessary further investigations.

RandomiSed clinical trial assessing Use of an anti-inflammatoRy aGent in attenUating peri-operatiVe inflAmmatioN in non-meTastatic colon cancer - the S.U.R.G.U.V.A.N.T. trial.

BACKGROUND: Peri-operative inflammation has been extensively highlighted in cancer patients as detrimental. Treatment strategies to improve survival for cancer patients through targeting peri-operative inflammation have yet to be devised. METHODS: We conducted a multi-centre, randomised controlled clinical trial using Taurolidine in non-metastatic colon cancer patients. Patients were randomly assigned to receive Taurolidine or a placebo. The primary endpoint for the study was the mean difference in day 1 IL-6 levels. Secondary clinical endpoints included rates of post-operative infections and tumor recurrence. RESULTS: A total of 293 patients were screened for trial inclusion. Sixty patients were randomised. Twenty-eight patients were randomised to placebo and 32 patients to Taurolidine. IL-6 levels were equivalent on day 1 post-operatively in both groups. However, IL-6 levels were significantly attenuated over the 7 day study period in the Taurolidine group compared to placebo (p = 0.04). In addition, IL-6 levels were significantly lower at day 7 in the Taurolidine group (p = 0.04). There were 2 recurrences in the placebo group at 2 years and 1 in the Taurolidine group. The median time to recurrence was 19 months in the Placebo group and 38 months in the Taurolidine group (p = 0.27). Surgical site infection was reduced in the Taurolidine treated group (p = 0.09). CONCLUSION: Peri-operative use of Taurolidine significantly attenuated circulating IL-6 levels in the initial 7 day post-operative period in a safe manner. Future studies are required to establish the impact of IL-6 attenuation on survival outcomes in colon cancer. TRIAL REGISTRATION: The trial was registered with EudraCT (year = 2008, registration number = 005570-12 ) and ISRCTN (year = 2008, registration number = 77,829,558 ).

Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER-/PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact?

Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.

Activation of the TLR2-mediated downstream signaling pathways NF-κB and MAPK is responsible for B7-H3-augmented inflammatory response during S. pneumoniae infection.

It has been reported that B7-H3, a costimulatory protein, participates in the development and progression of experimental pneumococcal meningitis by amplifying the TLR2-mediated inflammatory response. This study attempted to clarify the pathway(s) of TLR2 signaling involved in B7-H3-augmented inflammatory response during S. pneumoniae infection. Murine microglial cell line N9 cells and primary murine microglial cells were infected with S. pneumoniae alone or in combination with B7-H3. Although B7-H3 stimulation failed to further enhance S. pneumoniae-upregulated mRNA and protein expression of TLR2, it strongly augmented S. pneumoniae-induced phosphorylation of NF-κB p65, MAPK p38, and ERK1/2 in both N9 cells and primary microglial cells. Notably, B7-H3 itself did not activate NF-κB p65, MAPK p38, and ERK1/2. Furthermore, deactivation of NF-κB p65, MAPK p38, and ERK1/2 with their specific inhibitors significantly attenuated B7-H3-amplified proinflammatory cytokine and chemokine release from S. pneumoniae-infected microglial cells. Importantly, blockage of NF-κB p65, MAPK p38, or ERK1/2 in vivo substantially diminished B7-H3-augmented TNF-α levels in the brain of S. pneumoniae-infected mice. These results indicate that the activation of both NF-κB and MAPKs is predominantly responsible for B7-H3-augmented inflammatory response during S. pneumoniae infection.

B7H3 ameliorates LPS-induced acute lung injury via attenuation of neutrophil migration and infiltration.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by an excessive inflammatory response within the lungs and severely impaired gas exchange resulting from alveolar-capillary barrier disruption and pulmonary edema. The costimulatory protein B7H3 functions as both a costimulator and coinhibitor to regulate the adaptive and innate immune response, thus participating in the development of microbial sepsis and pneumococcal meningitis. However, it is unclear whether B7H3 exerts a beneficial or detrimental role during ALI. In the present study we examined the impact of B7H3 on pulmonary inflammatory response, polymorphonuclear neutrophil (PMN) influx, and lung tissue damage in a murine model of lipopolysaccharide (LPS)-induced direct ALI. Treatment with B7H3 protected mice against LPS-induced ALI, with significantly attenuated pulmonary PMN infiltration, decreased lung myeloperoxidase (MPO) activity, reduced bronchoalveolar lavage fluid (BALF) protein content, and ameliorated lung pathological changes. In addition, B7H3 significantly diminished LPS-stimulated PMN chemoattractant CXCL2 production by inhibiting NF-κB p65 phosphorylation, and substantially attenuated LPS-induced PMN chemotaxis and transendothelial migration by down-regulating CXCR2 and Mac-1 expression. These results demonstrate that B7H3 substantially ameliorates LPS-induced ALI and this protection afforded by B7H3 is predominantly associated with its inhibitory effect on pulmonary PMN migration and infiltration.

Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1.

The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155-binding sites in its 3'-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.

Current knowledge and future directions of TLR and NOD signaling in sepsis.

The incidence of sepsis is increasing over time, along with an increased risk of dying from the condition. Sepsis care costs billions annually in the United States. Death from sepsis is understood to be a complex process, driven by a lack of normal immune homeostatic functions and excessive production of proinflammatory cytokines, which leads to multi-organ failure. The Toll-like receptor (TLR) family, one of whose members was initially discovered in Drosophila, performs an important role in the recognition of microbial pathogens. These pattern recognition receptors (PRRs), upon sensing invading microorganisms, activate intracellular signal transduction pathways. NOD signaling is also involved in the recognition of bacteria and acts synergistically with the TLR family in initiating an efficient immune response for the eradication of invading microbial pathogens. TLRs and NOD1/NOD2 respond to different pathogen-associated molecular patterns (PAMPs). Modulation of both TLR and NOD signaling is an area of research that has prompted much excitement and debate as a therapeutic strategy in the management of sepsis. Molecules targeting TLR and NOD signaling pathways exist but regrettably thus far none have proven efficacy from clinical trials.

Social media and tomorrow's medical students--how do they fit?

OBJECTIVE: The main aim of our study was to establish the prevalence of social networking accounts among a group of second-level students (aged 15-18 years), to determine whether they used privacy settings, and to examine their attitudes to various aspects of social media use in medicine. DESIGN: A descriptive study design was employed. The questionnaire was constructed specifically to address the attitudes of students to social media. No similar suitable validated questionnaire could be identified. The questionnaire consisted of 20 questions with a mixture of open answer, yes/no, and Likert scale response options. PARTICIPANTS: Participation was voluntary and anonymous. Second-level school children interested in studying medicine and aged between 15 and 18 years took part. SETTING: An annual open day organized by the School of Medicine in University College Cork, Ireland, formed the setting. The day comprised a mixture of lectures, demonstrations, and practical sessions designed to give the students insight into life as a medical student. RESULTS: A total of 96 students attended, and all were handed the questionnaires. Of them, 88 students completed the survey. Overall, 90.9% of students had Facebook accounts and 53% had Twitter accounts. Of those with social media accounts, 14.8% reported having no privacy settings. Most respondents felt that unprofessional behavior on social media sites should be a factor considered in admission to medical schools. CONCLUSIONS: Serious consequences can result from lapses in best practice relating to social media behavior. Dedicated reflective learning modules need to be incorporated into undergraduate and postgraduate training programs as a matter of urgency.

The impact of childhood obesity on inflammation, innate immune cell frequency, and metabolic microRNA expression.

BACKGROUND: Obesity is characterized by chronic inflammation, immune dysregulation, and alteration of gene expression, associated with type 2 diabetes mellitus and cardiovascular disease. The degree to which these changes occur in childhood obesity is not fully defined. AIMS AND METHODS: The aim was to investigate the effect of childhood obesity on immune cell frequency, macrophage activation, cytokine production, and specific regulators of metabolic gene expression. Profiling was performed on peripheral blood from 29 obese and 20 nonobese children using real-time PCR, ELISA, and flow cytometry. RESULTS: Fasting glucose was similar in both groups, but there was a higher degree of insulin resistance in obese subjects (homeostasis model of assessment for insulin resistance, 4.8 vs 0.84; P < .001). Soluble CD163, a marker of macrophage polarization to a proinflammatory profile, was elevated in the obese compared to nonobese children (135 vs 105 ng/mL; P = .03). Invariant natural killer T cells were reduced in the obese children (CD3 T cells, 0.31 vs 0.53%; P = .001). Cytokine profiling revealed significantly elevated TNF-α (6.7 vs 5.1 pg/mL; P = .01) and leptin (1186 vs 432 pg/mL; P < .001) and reduced adiponectin (884 vs 1321 pg/mL; P = .001) in obese compared to nonobese children. Stimulation of peripheral blood mononuclear cells from obese children resulted in higher levels of IL-1ß (2100 vs 1500 pg/mL; P = .018). There was a 4-fold increase in expression of microRNA33a (P = .001) and a 3-fold increase in microRNA33b (P = .017) in obese children. CONCLUSION: Childhood obesity is associated with changes in immune cell frequency, inflammatory environment, and regulation of metabolic gene expression. These changes have been causally linked to the onset of metabolic disease in adulthood and suggest the future trajectory of obese children to the development of type 2 diabetes mellitus and premature cardiovascular disease.

Expressional alterations in functional ultra-conserved non-coding RNAs in response to all-trans retinoic acid--induced differentiation in neuroblastoma cells.

BACKGROUND: Ultra-conserved regions (UCRs) are segments of the genome (≥ 200 bp) that exhibit 100% DNA sequence conservation between human, mouse and rat. Transcribed UCRs (T-UCRs) have been shown to be differentially expressed in cancers versus normal tissue, indicating a possible role in carcinogenesis. All-trans-retinoic acid (ATRA) causes some neuroblastoma (NB) cell lines to undergo differentiation and leads to a significant decrease in the oncogenic transcription factor MYCN. Here, we examine the impact of ATRA treatment on T-UCR expression and investigate the biological significance of these changes. METHODS: We designed a custom tiling microarray to profile the expression of 481 T-UCRs in sense and anti-sense orientation (962 potential transcripts) in untreated and ATRA-treated neuroblastoma cell lines (SH-SY5Y, SK-N-BE, LAN-5). Following identification of significantly differentially expressed T-UCRs, we carried out siRNA knockdown and gene expression microarray analysis to investigate putative functional roles for selected T-UCRs. RESULTS: Following ATRA-induced differentiation, 32 T-UCRs were differentially expressed (16 up-regulated, 16 down-regulated) across all three cell lines. Further insight into the possible role of T-UC.300A, an independent transcript whose expression is down-regulated following ATRA was achieved by siRNA knockdown, resulting in the decreased viability and invasiveness of ATRA-responsive cell lines. Gene expression microarray analysis following knockdown of T-UC.300A revealed a number of genes whose expression was altered by changing T-UC.300A levels and that might play a role in the increased proliferation and invasion of NB cells prior to ATRA-treatment. CONCLUSIONS: Our results indicate that significant numbers of T-UCRs have altered expression levels in response to ATRA. While the precise roles that T-UCRs might play in cancer or in normal development are largely unknown and an important area for future study, our findings strongly indicate that the function of non-coding RNA T-UC.300A is connected with proliferation, invasion and the inhibition of differentiation of neuroblastoma cell lines prior to ATRA treatment.

miR-107: a toll-like receptor-regulated miRNA dysregulated in obesity and type II diabetes.

miRNAs are small noncoding RNAs that act as regulators of gene expression. Dysregulation of miRNAs has been shown to contribute to multiple disease processes. It has become apparent that miRNAs play a key role in the innate immune response, whereby a large number of miRNAs have been demonstrated to be regulated by TLRs, key initiators of the innate immune response to infection. Recently, the LPS receptor, TLR4, has been shown to down-regulate miR-107 in macrophages. In addition, miR-107 has been demonstrated to be dysregulated in murine and rodent models of obesity and insulin resistance, respectively, with miR-107 contributing to both conditions. With obesity and inflammation being so intrinsically associated, the link between the miR-107 expression levels, inflammation, and insulin resistance may be of particular importance in metabolic diseases. The decrease in miR-107 in response to TLR4 may be an attempt to limit insulin resistance, a feature of obesity-related inflammation. If this process is impaired, disease, such as T2D, might persist. This review aims to discuss a possible link between the molecular phenomena of obesity and inflammation and the role that miR-107 may contribute to these processes.

Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase A oncogene.

BACKGROUND: Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. RESULTS: As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. CONCLUSIONS: PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

MicroRNA and DNA methylation alterations mediating retinoic acid induced neuroblastoma cell differentiation.

Many neuroblastoma cell lines can be induced to differentiate into a mature neuronal cell type with retinoic acid and other compounds, providing an important model system for elucidating signalling pathways involved in this highly complex process. Recently, it has become apparent that miRNAs, which act as regulators of gene expression at a post-transcriptional level, are differentially expressed in differentiating cells and play important roles governing many aspects of this process. This includes the down-regulation of DNA methyltransferases that cause the de-methylation and transcriptional activation of numerous protein coding gene sequences. The purpose of this article is to review involvement of miRNAs and DNA methylation alterations in the process of neuroblastoma cell differentiation. A thorough understanding of miRNA and genetic pathways regulating neuroblastoma cell differentiation potentially could lead to targeted therapies for this disease.

MicroRNA-542-5p as a novel tumor suppressor in neuroblastoma.

Several studies have implicated the dysregulation of microRNAs in neuroblastoma pathogenesis, an often fatal paediatric cancer arising from precursor cells of the sympathetic nervous system. Our group and others have demonstrated that lower expression of miR-542-5p is highly associated with poor patient survival, indicating a potential tumor suppressive function. Here, we demonstrate that ectopic over-expression of this miRNA decreases the invasive potential of neuroblastoma cell lines in vitro, along with primary tumor growth and metastases in an orthotopic mouse xenograft model, providing the first functional evidence for the involvement of miR-542-5p as a tumor suppressor in any type of cancer.