Nannizzia incurvata in Hue city - Viet Nam: Molecular identification and antifungal susceptibility testing

BackgroundNannizzia incurvata, a species belonging to the Nannizzia gypsea complex, is considered a neglected pathogen.ObjectiveTo detected N. incurvata isolates from dermatophytosis patients in Hue city - Viet Nam, and test the antifungal susceptibility of this species. Moreover, fungal capability to produce hydrolytic enzymes was evaluated.MethodsPatients’ samples were collected and cultured on Sabouraud-chloramphenicol-cycloheximide medium. Dermatophytes isolates were initially macroscopically and microscopically identified. ITS PCR-RFLP and ITS rDNA sequences were performed to determine and confirm species. An ITS Neighbor-Joining phylogenetic tree evaluated the genetic relationship among isolates. Fungal hydrolytic enzymes were examined, including lipase, phospholipase and protease. Antifungal susceptibility testing was carried out by the disk diffusion method. MICs of itraconazole, voriconazole, and terbinafine against these isolates were determined by the broth microdilution method.ResultsTwelve isolates of N. gypsea complex were preliminary morphologically identified. PCR-RFLP and ITS-rDNA sequencing identified and confirmed dermatophytes as N. incurvata strains, respectively. An evident polymorphism among isolates was highlighted in the phylogenetic tree. All isolates showed the activity of lipase, phospholipase, and protease production. Overall, all N. incurvata isolates were susceptible to itraconazole, voriconazole, clotrimazole, miconazole, and terbinafine. Few isolates were susceptible to griseofulvin, and none of them were susceptible to fluconazole.ConclusionsThere was a presence of polyclonal N. incurvata isolates in dermatophytosis patients from Hue city, identified by PCR-RLFP and confirmed by ITS sequencing. We confirmed PCR-RLFP as a reliable technique to identify this species. Azole and terbinafine are the optimal choices for N. incurvata treatment except for fluconazole.     

Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion

The hepatocyte growth factor/scatter factor (HGF/SF) receptor, Met, mediates various cellular responses on activation with its ligand, including proliferation, survival, motility, invasion, and tubular morphogenesis. Met expression is frequently up-regulated in sarcomas and carcinomas. Experimental evidence suggests that Met activation correlates with poor clinical outcome and the likelihood of metastasis. Therefore, inhibitors of Met tyrosine kinase may be useful for the treatment of a wide variety of cancers that have spread from the primary site. We have discovered potent and selective pyrrole-indolinone Met kinase inhibitors and characterized them for their ability to inhibit HGF/SF-induced cellular responses in vitro. These compounds inhibit HGF/SF-induced receptor phosphorylation in a dose-dependent manner. They also inhibit the HGF/SF-induced motility and invasion of epithelial and carcinoma cells. Therefore, these compounds represent a class of prototype small molecules that selectively inhibit the Met kinase and could lead to identification of compounds with potential therapeutic utility in treatment of cancers.     

Trastuzumab for early breast cancer: current status and future directions

The human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in up to 25% of breast cancer patients, and this feature is associated with an aggressive phenotype, a high recurrence rate, and reduced survival. Until recently, combination chemotherapy was the most effective and only adjuvant treatment for HER2-positive patients. Trastuzumab, a monoclonal antibody directed against the HER2 extracellular domain, has recently demonstrated highly reproducible and astonishing benefit in halving the recurrence rate and reducing mortality in five adjuvant breast cancer trials. But such unfettered success has come at a cost, both in terms of cardiotoxic risk and substantial financial burden. Though trastuzumab has been able to significantly improve clinical outcomes of many patients with early breast cancer, the reality is that an unacceptable proportion will still relapse. Beyond trastuzumab, what is the next step for these HER2-positive breast cancers? This review first discusses the individual results of the five adjuvant trastuzumab studies in terms of efficacy and safety, highlighting their similarities and differences. It also evaluates the current status of trastuzumab as a result of these studies and explores the possible future direction for HER2-positive breast cancers in light of recent advances in translational oncology.     

Custom CAD/CAM implants for complex craniofacial reconstruction in children: Our experience based on 136 cases✰

Background

CAD-CAM patient-specific implants offer cerebral protection and improved facial balance without the disadvantages of autologous bone grafting such as donor site morbidity and unpredictable resorption. Several alloplastic materials are available, but titanium, polymethylmethacrylate (PMMA), and polyetheretherketone (PEEK) are the current popular choices. We reviewed our experience of applying different alloplastic CAD-CAM materials in the reconstruction of complex pediatric craniofacial deformities.

Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis

Lymphatic tissues (LTs) are structurally organized to promote interaction between antigens, chemokines, growth factors, and lymphocytes to generate an immunologic response and maintain normal-sized populations of CD4(+) and CD8(+) T cells. Inflammation and tissue remodeling that accompany local innate and adaptive immune responses to HIV-1 replication cause damage to the LT architecture. As a result, normal populations of CD4(+) and CD8(+) T cells cannot be supported and antigen-lymphocyte interactions are impaired. This conclusion is supported herein following LT sampling before and during anti-HIV therapy in persons with acute, chronic, and late-stage HIV-1 infection. Among seven individuals treated with anti-retroviral therapy (ART) and four individuals deferring therapy we found evidence of significant paracortical T cell zone damage associated with deposition of collagen, the extent of which was inversely correlated with both the size of the LT CD4(+) T cell population and the change in peripheral CD4(+) T cell count with anti-HIV therapy. The HIV-1-associated inflammatory changes and scarring in LT both limit the ability of the tissue to support and reestablish normal-sized populations of CD4(+) T cells and suggest a novel mechanism of T cell depletion that may explain the failure of ART to significantly increase CD4(+) T cell populations in some HIV-1-infected persons.     

CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract

The mechanisms underlying CD4(+) T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4(+) and CD8(+) T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4(+) T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5(+) CD4(+) T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4(+) T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5(+) CD4(+) T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.     

Effect of peripheral endothelin‐1 concentration on carcinoma‐induced pain in mice

In this study, we investigated the role of the peripheral endothelin‐1 (ET‐1) concentration in a cancer pain model. To test the hypothesis that the concentration of ET‐1 in the tumor microenvironment is important in determining the level of cancer pain we used two cancer pain mouse models that differed significantly in production of ET‐1. The two mouse cancer models were produced by injection of cells derived from a human oral squamous cell carcinoma (SCC) and melanoma into the hind paw of female mice. Pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, was significantly greater in the SCC group than the melanoma group. The peripheral concentration of ET‐1 within the cancer microenvironment was significantly greater in the SCC group. Intra‐tumor expression of both ET‐1 mRNA and ET‐1 protein were significantly higher in the SCC model compared to the melanoma model. ET receptor antagonism was effective as an analgesic for cancer pain in the SCC model only. To address the potential confounding factor of tumor volume we evaluated the contribution of tumor volume to cancer pain in the two models. The mean volumes of the tumors in the melanoma group were significantly greater than the tumors in the SCC group. In both groups, the pain level correlated with tumor volume, but the correlation was stronger in the melanoma group. We conclude that ET‐1 concentration is a determinant of the level of pain in a cancer pain mouse model and it is a more important factor than tumor volume in producing cancer pain. These results suggest that future treatment regimens for cancer pain directed at ET‐1 receptor antagonism show promise and may be tumor type specific.     

Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg‐negative and anti‐HBc antibodies‐positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer

Summary. We studied clinical outcome and clinico‐virological factors associated with hepatitis B virus reactivation (HBV‐R) following cancer treatment in hepatitis B virus surface antigen (HBsAg)‐negative/anti‐hepatitis B core antibodies (anti‐HBcAb)‐positive patients. Between 11/2003 and 12/2005, HBV‐R occurred in 7/84 HBsAg‐negative/anti‐HBcAb‐positive patients treated for haematological or solid cancer. Virological factors including HBV genotype, core promoter, precore, and HBsAg genotypic and amino acid (aa) patterns were studied. Patients presenting with reactivation were men, had an hepatitis B virus surface antibody (HBsAb) titre <100 IU/L and underwent >1 line of chemotherapy (CT) significantly more frequently than controls. All were treated for haematological cancer, 3/7 received haematopoietic stem cell transplantation (HSCT), and 4/7 received rituximab. Using multivariate analysis, receiving >1 line of CT was an independent risk factor for HBV‐R. Fatal outcome occurred in 3/7 patients (despite lamivudine therapy in two), whereas 2/4 survivors had an HBsAg seroconversion. HBV‐R involved non‐A HBV genotypes and core promoter and/or precore HBV mutants in all cases. Mutations known to impair HBsAg antigenicity were detected in HBV DNA from all seven patients. HBV DNA could be retrospectively detected in two patients prior cancer treatment and despite HBsAg negativity. HBV‐R is a concern in HBsAg‐negative/anti‐HBcAb‐positive patients undergoing cancer therapy, especially in males presenting with haematological cancer, a low anti‐HBsAb titre and more than one chemotherapeutic agent. HBV DNA testing is mandatory to improve diagnosis and management of HBV‐R in these patients. The role of specific therapies such as rituximab or HSCT as well as of HBV aa variability deserves further studies.