Significant association of high-risk human papillomavirus (HPV) but not of p53 polymorphisms with oral squamous cell carcinomas in Malaysia

Purpose  

The purpose of this study was to evaluate the role of HPV and p53 polymorphisms in oral squamous cell carcinomas (OSCC) affecting Malaysian population.     

Comparative antifungal activity of cilofungin (LY121019) against Candida species, including evaluation of susceptibility testing method

The in vitro activity of cilofungin against 100 Candida species was compared with 5-flucytosine. amphotericin B and ketoconazole by two laboratories independently and in a blinded fashion using a macrotitre dilution broth method in saam-f medium. Cilofungin showed good in vitro activity against Candida albicans. Candida tropicalis and Candida glabrata (90% minimal inhibitory concentration [MIC] 3.2 μg/mL) but was inactive against other Candida species. When testing the susceptibility of cilofungin, 5-flucytosine and amphotericin B at the two centres, approximately 90% of the Candida strains had MICs differing by fourfold or less. However, when testing susceptibility of ketoconazole, only 51% of the Candida strains had MIC differences fourfold or less. MIC susceptibility testing with cilofungin, 5-flucytosine and amphotericin B in saam-f medium is reproducible.     

Reversible Blindness as Presenting Manifestation of Severe Diabetic Ketoacidosis

The presenting symptoms of diabetic ketoacidosis (DKA) include abdominal pain, polyuria and nausea. Diabetes has well known chronic ocular complications like glaucoma, cataracts and retinopathy. We report a case of reversible blindness as a presenting manifestation of DKA that has been reported in literature only 3 times previously. Our objective is to highlight a rare manifestation of a common disease. A 59-year-old male presented with painless vision loss for 3 days and was found to have DKA. The blindness was completely reversed with insulin and bicarbonate treatment. The dramatic presentation and reversibility of blindness was found to be intimately tied with the pH of the patient's serum. Our report gives mechanistic insight for this interesting condition. Clinicians should be aware of reversible blindness as a complication of DKA. Timely correction of the severe acidosis and other metabolic disturbances of DKA may be instrumental in preventing permanent vision loss.     

Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells

Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume(12) greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G(2)M and increased pre-G(o) DNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.     

Targeted treatment and new agents in peripheral T-cell lymphoma

Mature T-cell and NK-cell lymphomas are increasingly being recognized as unique biological entities distinguishable from other forms of lymphomas. Treatment paradigms developed for B-cell lymphomas are considered inadequate for application to these diseases, as indicated by the poor outcome of these patients with the overall 5-year survival remaining below 30% for most histologies. There is a tremendous need for newer treatment options both in the upfront and relapsed setting for T-cell lymphomas. In recent years, there has been a plethora of new targeted agents that have shown promising activity in T-cell lymphomas. The most notable is the novel antifolate pralatrexate that has been approved for the treatment of relapsed and refractory T-cell lymphoma. Other agents include histone deacetylase inhibitors (vorinostat, romidepsin, belinostat), proteosome inhibitors (bortezomib), immunomodulatory agents (lenalidomide), nucleoside analogs (gemcitabine, nalarabine) and targeted antibodies. An improved understanding of the molecular pathogenesis of T-cell lymphomas will help define the role of these agents in the treatment paradigms of T-cell lymphomas both as single agents and as rationally designed combinations and will lead to curative treatments for these difficult diseases.     

Basement membrane and the SIKVAV laminin-derived peptide promote tumor growth and metastases

Summary Laminin, the major glycoprotein component of basement membrane, promotes the malignant phenotype. Cells which are adherent to laminin are more malignant than the non-adherent cells and in certain tumor cells, the number of laminin receptors is positively correlated with malignancy. Laminin also increases collagenase IV activity, an enzyme demonstrated to be critical for tumor spread. A site on laminin, containing the amino acid sequence SIKVAV, has been identified which when injected intravenously with B16F10 melanoma cells, causes an increase in the number of colonies on the surface of the lungs. This peptide does not affect tumor cell arrest in the vasculature or the immune system. It does promote angiogenesis in various in vitro and in vivo models, thereby facilitating tumor cell survival.When a complex mixture of laminin-enriched basement membrane components (Matrigel) is coinjected with tumor cells subcutaneously, tumor incidence and growth increases. Various tumor cell lines and primary isolates, which previously could not form tumors in mice, can be induced to grow rapidly in the presence of Matrigel. Slowly growing tumors or arrested tumors can also be induced to grow more quickly with additional injections of Matrigel. When an SIKVAV-containing synthetic peptide is coinjected with B16F10 tumor cells and Matrigel subcutaneously in mice, larger tumors are formed than that observed with either Matrigel or cells alone. Such studies define the role of laminin in tumor growth and spread and generate new models for studying therapeutic agents. Of particular interest is the ability to grow primary isolates which generally do not grow in mice.     

Establishment and characterization of Asian oral cancer cell lines as in vitro models to study a disease prevalent in Asia

We have established 3 cell lines ORL-48, -115 and -136 from surgically resected specimens obtained from untreated primary human oral squamous cell carcinomas of the oral cavity. The in vitro growth characteristics, epithelial origin, in vitro anchorage independency, human papilloma-virus (HPV) infection, microsatellite instability status, karyotype and the status of various cell cycle regulators and gatekeepers of these cell lines were investigated. All 3 cell lines grew as monolayers with doubling times ranging between 26.4 and 40.8 h and were immortal. Karyotyping confirmed that these cell lines were of human origin with multiple random losses and gains of entire chromosomes and regions of chromosomes. Immunohistochemistry staining of cytokeratins confirmed the epithelial origin of these cell lines, and the low degree of anchorage independency expressed by these cell lines suggests non-transformed phenotypes. Genetic analysis identified mutations in the p53 gene in all cell lines and hypermethylation of p16INK4a in ORL-48 and -136. Analysis of MDM2 and EGFR expression indicated MDM2 overexpression in ORL-48 and EGFR overexpression in ORL-136 in comparison to the protein levels in normal oral keratinocytes. Analysis of the BAT-26 polyadenine repeat sequence and MLH-1 and MSH-2 repair enzymes demonstrated that all 3 cell lines were microsatellite stable. The role of HPV in driving carcinogenesis in these tumours was negated by the absence of HPV. Finally, analysis of the tissues from which these cell lines were derived indicated that the cell lines were genetically representative of the tumours, and, therefore, are useful tools in the understanding of the molecular changes associated with oral cancers.     

MRI radiomics to differentiate between low grade glioma and glioblastoma peritumoral region

Journal of Neuro-Oncology - Primary malignant spinal astrocytomas present rare oncological entities with limited median survival and rapid neurological deterioration. Evidence on surgical therapy,...