MicroRNA-687 Induced by Hypoxia-Inducible Factor-1 Targets Phosphatase and Tensin Homolog in Renal Ischemia-Reperfusion Injury

Ischemia-reperfusion injury contributes to tissue damage and organ failure in clinical settings, but the underlying mechanism remains elusive and effective therapies are still lacking. Here, we identified microRNA 687 (miR-687) as a key regulator and therapeutic target in renal ischemia-reperfusion injury. We show that miR-687 is markedly upregulated in the kidney during renal ischemia-reperfusion in mice and in cultured kidney cells during hypoxia. MiR-687 induction under these conditions was mediated by hypoxia-inducible factor-1 (HIF-1). Upon induction in vitro, miR-687 repressed the expression of phosphatase and tensin homolog (PTEN) and facilitated cell cycle progression and apoptosis. Blockade of miR-687 preserved PTEN expression and attenuated cell cycle activation and renal apoptosis, resulting in protection against kidney injury in mice. Collectively, these results unveil a novel HIF-1/miR-687/PTEN signaling pathway in ischemia-reperfusion injury that may be targeted for therapy.     

An assessment of deprivation as a factor in the delays in presentation, diagnosis and treatment in patients with oral and oropharyngeal squamous cell carcinoma

This study explores the relationship between deprivation and patient and professional delays in presentation and treatment of oral and oropharyngeal squamous cell carcinoma. The cohort comprised 559 consecutive previously untreated patients presenting to the Regional Maxillofacial Unit, Liverpool from 1 January 1992 to 31 December 2002. All had primary surgery. The head and neck database was searched together with a review of casenotes. Deprivation was scored using the Index of Multiple Deprivation 2000 (IMD 2000) from patient post codes. PATIENT DELAY: Similar numbers of patients presented to general dental and general medical practitioners. The predominant presenting symptom was either an ulcer or swelling and 38% had symptoms for 3 or more months. Patients with shorter duration of symptoms tended to be smokers, drinkers, with lower gum and floor of mouth tumours, and more advanced disease. Primary health professional, patient age, gender, marital status, and deprivation showed no obvious correlation with patient delay. PROFESSIONAL DELAY: For 78% of patients a referral letter from GPs and GDPs was sent to the MFU on the same day as the primary consultation. There was on average about 3 weeks from referral to definitive diagnosis and about another 3 weeks before having surgery. Professional delay was shorter in patients with more advanced tumours and for patients living in the most deprived of wards. Deprivation did not seem to significantly lengthen presentation or referral however it may be that it is associated with more rapidly growing tumours.     

The management of otitis externa in UK general practice

Acute otitis externa is common and provides a heavy workload for general practitioners. We aim to determine the first-line treatment used by general practitioners in the management of otitis externa and subsequent second-line treatment in a hospital ENT clinic. In addition, this study aims to ascertain whether local and national guidelines are being followed appropriately. A prospective observational study on the management of otitis externa in consecutive patients referred to an ENT emergency clinic was undertaken. Data were collected and analysed on symptoms, initial management by general practitioners, findings and treatment in the ENT clinic. A total of 106 patients were studied. The mean duration of symptoms before presentation to clinic was 13 days; 42% of patients received no treatment by their GP prior to referral to the ENT emergency clinic. Only 14% of patients received topical antibiotics alone, whilst 44% received oral antibiotics, either alone or in conjunction with topical antibiotics by their GP. Of the 106 patients, 86% received topical antibiotics in the ENT emergency clinic and oral antibiotics were reserved for those presenting with complicated acute otitis externa. Topical antibiotics are associated with a decrease in disease persistence, whilst oral antibiotics are associated with an increase. However, general practitioners are prescribing oral antibiotics more often than required. There are few regional guidelines and no explicit national guidelines on the management of acute otitis externa for GPs to refer to. We suggest the implementation of national guidelines to aid clinical practice.     

Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+)

Studies in post-mortem tissues of patients with Parkinson’s disease (PD) and in mice treated with 6-hydroxydopamine have shown a decrease in the length of axon and dendrites of striatal neurons. However, the etiology of the morphological changes and their relationship to inhibition of mitochondrial complex I and the cellular levels of iron and glutathione (GSH) have not been described. In this study, we characterized the effect of MPP+, an inhibitor of mitochondria complex I, on the integrity of the neuritic tree of midbrain dopaminergic neurons, and determined the influence of iron and cellular levels of GSH on this degeneration. Sub-maximal concentrations of MPP+ induced a drastic dose-dependent reduction of neurites, without modification of the soma or apparent cell death. Concurrent treatment with MPP+ and non-toxic concentrations of iron accelerated the process of degeneration, whereas neurons grown on a medium low in iron showed enhanced resistance to MPP+ treatment. MPP+-induced neurite shortening depended on the redox state of neurons. Pre-treatment with the general antioxidant N-acetyl cysteine protected neurons from degeneration. Treatment with sub-maximal concentrations of the inhibitor of GSH synthesis buthionine sulfoximine (BSO), in conjunction with iron and MPP+, produced massive cell death, whereas treatment with BSO plus MPP+ under low iron conditions did not damage neurons. These results suggest that under conditions of inhibition of mitochondrial complex I caused by MPP+, the accumulation of iron and the concurrent decrease in GSH results in the loss of the dendritic tree prior to cell death, of dopaminergic neurons in PD.     

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo: procoagulant nature of osteosarcoma

BACKGROUND:

Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth.

METHODS:

Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell‐based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor‐dependent thrombin generation and growth in vitro and in vivo was determined.

RESULTS:

Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo.

CONCLUSIONS:

These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin. Cancer 2012. © 2011 American Cancer Society.     

Colon cancer and the epidermal growth factor receptor: Current treatment paradigms,the importance of diet,and the role of chemoprevention

Colorectal cancer represents the third most common and the second deadliest type of cancer for both men and women in the United States claiming over 50000 lives in 2014. The 5-year survival rate for patients diagnosed with metastatic colon and rectal cancer is < 15%. Early detection and more effective treatments are urgently needed to reduce morbidity and mortality of patients afflicted with this disease. Here we will review the risk factors and current treatment paradigms for colorectal cancer, with an emphasis on the role of chemoprevention as they relate to epidermal growth factor receptor (EGFR) blockade. We will discuss how various EGFR ligands are upregulated in the presence of Western diets high in saturated and N-6 polyunsaturated fats. We will also outline the various mechanisms of EGFR inhibition that are induced by naturally occurring chemopreventative agents such as ginseng, green tea, and curcumin. Finally, we will discuss the current role of targeted chemotherapy in colon cancer and outline the limitations of our current treatment options, describing mechanisms of resistance and escape.