The HMGA1-COX-2 axis: A key molecular pathway and potential target in pancreatic adenocarcinoma

ContextAlthough pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions.MethodsHere, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis.ResultsHMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r² = 0.93; p < 0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1.ConclusionsOur studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.     

Campylobacter colitis in a young child

This report describes a three-year old boy with serological, bacteriological and histological evidence of a colitis caused by Campylobacter jejuni. Symptomatic and histological recovery followed immediately the erradication of Campylobacter jejuni from the faeces by erythromycin. The history is suggestive of a chronic or recurrent infection with onset at 11 months.     

Effects of influx of holidaymakers on an acute medical unit in Cornwall.

This paper illustrates the effect of a large influx of holidaymakers on a medical unit in Cornwall. Increasing numbers of visitors are coming to Cornwall and, unless adequate resources are allocated for their efficient medical care, the medical facilities available to the residents will suffer greatly.     

PARTICLE SIZE STABILITY OF INTRALIPID AND MIXED TOTAL PARENTERAL NUTRITION MIXTURES

The determination of the particle size of Intralipid fat emulsions by the nonperturbing method of photon correlation spectroscopy has been extended to include particle size determination using the Coulter counter and optical microscopy. Although little increase in particle size in 3-litre bags containing total parenteral nutrition mixtures was observed with the methods involving large dilutions, creaming was observed and optical microscopy showed aggregation and some coalescence to have taken place. The problem of re-dispersion upon dilution of aggregated (but not coalesced) fat emulsions makes direct optical observation essential in assessing the stability and safety of such fat emulsion mixtures. The effect of electrolytes (NaCl and CaCl²) on creaming, particle size and electrophoretic mobility showed both minimum stability and minimum zeta potential at 3 × 10^-3mol dm-3 CaCl²and at 2. 5 × 10^-1mol dm^-3NaCl. Thus, these maximum levels for electrolytes in total parenteral mixtures are indicated.     

Cardiac,Hepatic and Renal Dysfunction and IL-18 Polymorphism in Breast,Colorectal, and Prostate Cancer Patients

Introduction: The present study aimed to determine the alterations in the serum levels of tumor markers used to evaluate cardiac, renal and liver function, and detect the interleukin (IL)-18 rs1946518 polymorphism in breast (BC), colorectal (CRC) and prostate cancer (PCa) patients. Methods: Blood samples were collected from 65 female BC, 116 CRC, 79 PCa and 88 myocardial infarction (MI) patients, and 110 healthy individuals to determine the concentration of tumor and cardiac markers. Furthermore, the IL-18 rs1946518 polymorphism was assessed using amplification refractory mutation system (ARMS)-PCR. Results: The serum levels of the tumor markers cancer antigen 15-3 (CA 15-3), carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and total prostate-specific antigen (TPSA) were significantly increased in cancer patients compared with healthy controls. Furthermore, the activity of high-sensitivity cardiac troponin T (hs-cTnT) and creatine kinase‑myocardial band (CK-MB) was enhanced in MI patients, however, their activity was unchanged in cancer patients. The activity of alkaline phosphatase (ALP), and the serum concentration of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea were markedly elevated in CRC and PCa patients, respectively, compared with the control group. Although, no significant differences were observed in the -607 C/A polymorphism and allele frequency of IL-18 among BC, CRC patients and healthy individuals, the odds ratio (OR) was 1.75 for both C and A allele in BC patients. Therefore, the -607 C/A polymorphism could be considered as a risk factor for BC. Conclusion: The aforementioned results suggested that tumor markers could be considered as excellent biomarkers for the early detection of BC, CRC and PCa, whereas the concentration of liver enzymes could serve as an alternative indicator for the diagnosis of CRC and PCa. Additionally, the rs1946518 polymorphism in the IL-18 gene could be considered as a risk factor for the occurrence of BC, CRC and PCa.     

Clinical significance of autoantibodies recognizing Sjögren's syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjögren's syndrome

The aim of our study was (i) to compare the clinical and biological characteristics of 148 (137 women, 11 men) primary Sjögren's syndrome (pSS) patients at diagnosis as a function of their sex and (ii) to assess the prognostic value of anti‐calpastatin and anti‐alpha‐fodrin autoantibodies. In addition, the presence of anti‐nuclear antibodies (ANA), anti‐52‐ and 60‐kDa Sjögren's syndrome A (SSA), anti‐Sjögren's syndrome B (SSB), anti‐cyclic citrullinated peptide (CCP) antibodies and rheumatoid factors (RF) of IgA, IgG and IgM isotypes was sought in sera collected at pSS onset. Raynaud's syndrome, significantly more frequent in women, was the only systemic manifestation of pSS whose frequency differed significantly as a function of the patient's sex (P = 0·02). ANA (P = 0·001) and anti‐60‐kDa SSA autoantibodies (P = 0·03) were significantly more common in women, while men never synthesized detectable levels of anti‐SSB, anti‐calpastatin or IgG anti‐alpha‐fodrin autoantibodies. In addition, anti‐CCP autoantibodies were found in low percentages of pSS patients (4% F/18% M). The absence of autoantibodies does not exclude the diagnosis of pSS in men that will be based mainly on the anatomopathological findings of a minor salivary gland biopsy. Positivity of anti‐60‐kDa SSA, anti‐SSB, anti‐calpastatin, IgA and IgG anti‐alpha‐fodrin antibodies is not associated with pSS clinical and biological severity.