Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma

The pathogenesis of BCC is associated with sonic hedgehog (SHH) signaling. Vismodegib, a smoothened inhibitor that targets this pathway, is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. We studied gene expression profiling of BCC tumour tissues coupled with laser capture microdissection to identify tumour specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. We found a >250 fold increase (FDR<10⁻⁴) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger expression of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 (members of SHH-pathway) mRNA by approximately 60% and 20%, respectively (p<0.01). Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promote keratinocyte proliferation. Hence, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.     

Asymmetrical distribution of beta-endorphin in cerebral hemispheres of suicides: preliminary data

The assessment of beta-endorphin levels in several symmetrical brain regions of seven suicides and seven sudden death controls reveals a decreased concentration in the left temporal cortex, the left frontal cortex, and the left caudate nucleus of suicides compared to controls. Moreover, the comparisons of beta-endorphin concentrations in the symmetrical brain regions reveals an asymmetrical concentration in suicides (left less than right) in frontal cortex and caudate nucleus. These data confirm previous reports of abnormalities of neurochemical pathways in the brains of suicides and suggest that suicidal behavior might be related to the lateralized mechanisms of mood control.     

Squamous cell carcinoma in organ transplant recipients: approach to management

Skin cancer, particularly squamous cell carcinoma (SCC), continues to be a significant cause of morbidity and even mortality in organ transplant recipients (OTRs). As the number of organ transplant patients continues to increase, dermatologists will be faced with the challenge of diagnosing and managing their skin cancers. Evaluation, management and follow up of organ transplant recipients with high risk SCC will be discussed.     

Upper gastrointestinal tract barium examination of postbulbar duodenal ulcers

OBJECTIVE: The purpose of our investigation was to review the findings on barium studies in a series of eight patients with postbulbar duodenal ulcers in order to better characterize the clinical and radiographic features of these ulcers. CONCLUSION: Our experience suggests that ulcers in the postbulbar duodenum are considerably larger than those in the duodenal bulb and that they constitute a greater percentage of all duodenal ulcers than has previously been recognized. It is important for radiologists to be familiar with the characteristic radiographic features of postbulbar ulcers because of the increased risk of serious upper gastrointestinal tract bleeding in patients with this condition.     

Bronchobiliary fistula after liver transplantation

This report describes the imaging findings of the first reported case of a bronchobiliary fistula that developed as a complication of liver transplantation. The diagnosis was confirmed by the aspiration of bile from the bronchus.     

Vaxfectin enhances immunogenicity and protective efficacy of P. yoelii circumsporozoite DNA vaccines

We evaluated the capacity of the cationic lipid based formulation, Vaxfectin, to enhance the immunogenicity and protective efficacy of DNA-based vaccine regimens in the Plasmodium yoelii murine malaria model. We immunized Balb/c mice with varying doses (0.4-50 microg) of plasmid DNA (pDNA) encoding the P. yoelii circumsporozoite protein (PyCSP), either in a homologous DNA/DNA regimen (D-D) or a heterologous prime-boost DNA-poxvirus regimen (D-V). At the lowest pDNA doses, Vaxfectin substantially enhanced IFA titers, ELISPOT frequencies, and protective efficacy. Clinical trials of pDNA vaccines have often used low pDNA doses based on a per kilogram weight basis. Formulation of pDNA vaccines in Vaxfectin may improve their potency in human clinical trials.     

Immunopathogenesis of hepatitis B virus recurrence after liver transplantation

BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.     

Radiographic imaging of inflammatory bowel disease

Radiographic imaging studies have an important role in the workup of patients with suspected IBD and in the differentiation of ulcerative colitis and Crohn's disease. Because of its ability to depict fine mucosal detail, the double-contrast barium study is a valuable technique for diagnosing ulcerative colitis and Crohn's disease even in patients with early disease. In contrast, cross-sectional imaging studies such as CT, MR, and ultrasound are useful for showing the effects of these conditions on the wall of the bowel and also for demonstrating intra-abdominal abscesses and other extraluminal findings in patients with more advanced disease. Thus, barium studies and cross-sectional imaging studies have complementary roles in the evaluation of these patients.     

Sequencing the genome of Plasmodium falciparum

Advances in microbial genomic sequencing have the potential to revolutionize the control of infectious diseases. Recently, a consortium of researchers and funding agencies from the United States and Great Britain have embarked on a project to sequence the genome from Plasmodium falciparum, the most important cause of human malaria. The Malaria Genome Sequencing Project has reached an important milestone with the completion of the entire DNA sequence and annotation of chromosome 2, a 950 kilobase chromosome of Plasmodium falciparum. This review article will provide an overview of the malaria genome sequencing project, highlight progress in the field of microbial sequencing, and suggest new directions for future malaria research.