Despite considerable progress being made in understanding pancreatic cancer (PC) pathogenesis, it still remains the 10th most often diagnosed malignancy in the world and 4th leading cause of cancer related deaths in the United States with a five year survival rate of only 6%. The aggressive nature, lack of early diagnostic and prognostic markers, late clinical presentation, and limited efficacy of existing treatment regimens makes PC a lethal cancer with high mortality and poor prognosis. Therefore, novel reliable biomarkers and molecular targets are urgently needed to combat this deadly disease. MicroRNAs (miRNAs) are short (19–24 nucleotides) non-coding RNA molecules implicated in the regulation of gene expression at post-transcriptional level and play significant roles in various physiological and pathological conditions. Aberrant expression of miRNAs has been reported in several cancers including PC and is implicated in PC pathogenesis and progression, suggesting their utility in diagnosis, prognosis and therapy. In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4 etc) involved in PC development, their prospective roles as diagnostic and prognostic markers and their therapeutic targets.

Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by pulmonary tissue that influence alveolar type (AT) II-ATI transition required for normal alveolar formation. However, the precise contribution of RAGE in interactions between pulmonary epithelium and splanchnic mesenchyme during lung organogenesis remains uncertain. To test the hypothesis that RAGE misexpression adversely affects lung morphogenesis, conditional transgenic mice were generated that overexpress RAGE. Mice that overexpress RAGE throughout embryogenesis experienced 100% mortality and significant lung hypoplasia coincident with large, vacuous areas in the periphery when compared with normal airway and alveolar architecture observed in control mouse lungs. Flow cytometry and immunohistochemistry employing cell-specific markers for distal (forkhead box protein A2) and respiratory (thyroid transcription factor-1) epithelium, ATII cells (pro-surfactant protein-C), and ATI cells (T1-α) demonstrated anomalies in key epithelial cell populations resulting from RAGE up-regulation. These results reveal that precise regulation of RAGE expression is required during lung formation. Furthermore, abundant RAGE results in profound alterations in epithelial cell differentiation that culminate in severe respiratory distress and perinatal lethality.

Heterozgyous spondyloepiphyseal dysplasia congenita (sedc/+) mice expressing a missense mutation in col2a1 exhibit a normal skeletal morphology but early-onset osteoarthritis (OA). We have recently examined knee articular cartilage obtained from homozygous (sedc/sedc) mice, which express a Stickler-like phenotype including dwarfism. We examined sedc/sedc mice at various levels to better understand the mechanistic process resulting in OA. Mutant sedc/sedc, and control (+/+) cartilages were compared at two, six and nine months of age. Tissues were fixed, decalcified, processed to paraffin sections, and stained with hematoxylin/eosin and safranin O/fast green. Samples were analyzed under the light microscope and the modified Mankin and OARSI scoring system was used to quantify the OA-like changes. Knees were stained with 1C10 antibody to detect the presence and distribution of type II collagen. Electron microscopy was used to study chondrocyte morphology and collagen fibril diameter. Compared with controls, mutant articular cartilage displayed decreased fibril diameter concomitant with increases in size of the pericellular space, Mankin and OARSI scores, cartilage thickness, chondrocyte clustering, proteoglycan staining and horizontal fissuring. In conclusion, homozygous sedc mice are subject to early-onset knee OA. We conclude that collagen in the mutant’s articular cartilage (both heterozygote and homozygote) fails to provide the normal meshwork required for matrix integrity and overall cartilage stability.

Background:In rheumatic and musculoskeletal diseases (RMDs), peripheral neurons can be affected, which can result in sensory symptoms like pain, burning, tingling, numbness and motor symptoms like muscle-atrophy or even paresis. More detailed knowledge about the prevalence and the cause of neuropathy (NP) in RMD are urgently needed, especially as RMD patients may develop different subtypes of NP.Objectives:The aim of this project was to assess the prevalence and the individual types of NP in rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic sclerosis (SSc) patients, and to elucidate the clinical, neurophysiological and neuropathologic features of associated NP.Methods:Baseline questionnaires and neurological and physical examination were used to elucidate the presence of neuropathic pain and autonomic dysfunction. Laboratory tests were performed to exclude other causes for NP. Electrophysiological tests were performed to differentiate demyelinating from axonal large fiber (LF)NPs. Additionally, skin biopsies were used to detect an involvement of small fibres (SF).Results:A total of 31 patients (median age 64 years (range 43-75)) were included. The majority of patients were female (90%). The mean disease duration was 10 years (1-41 years). More than 50% of the patients were diagnosed with RA, 7 with SpA and 6 with SSc. Of 31 patients, 48% (15/31) had clinical signs of NP and of those, neurophysiological examination showed 14 axonal 2, demyelinating and 4 mixed types. A combined LFNP and SFNP was present in 35% (11/31) of the patients. In 4 patients, only a SFNP was detectable, and in only two patients, no NP was detectable.Conclusion:NP was detectable in 94% (29/31) of the RMD patients, with LFNP predominating. This high proportion of NP in RMD suggests a surprisingly high coincidence of both diseases.Table 1.Subtypes of NP in RMDNumber of patientsAxonal NP14/31 (45%)Demyelinating NP2/31 (6%)Mixed axonal and demyelinating NP4/31 (12%)Sensory NP9/31 (26%)Sensorimotor NP5/31 (10%)Motor NP1/31 (3%)Disclosure of Interests:None declared.

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