Is clinical radiosensitivity a complex genetically controlled event?

New insights into molecular mechanisms responsible for cellular radiation response are coming from recent basic radiobiological studies. Preliminary data supporting the concept of clinical radiosensitivity as a complex genetically controlled event are available, and it seems reasonable to hypothesize that genes encoding for proteins implicated in known radiation-induced pathways, such as DNA repair, could influence normal tissue and tumor response to radiotherapy. Such genes could be considered as candidates for experimental studies and as targets for innovative therapies. Variants that could influence individual radiosensitivity have been recently identified, and specific Single Nucleotide Polymorphisms have been associated to the development of different radiation effects on normal tissues. Allelic architecture of complex traits able to modify phenotypes is difficult to be established, and different grades of interaction between common or rare genetic determinants may be present and should be considered. Many different experimental strategies could be investigated in the future, such as analysis of multiple genes in large irradiated patient cohorts strictly observed for radiation effects or identification of new candidate genes, with the aim of identifying factors that could be employed in predictive testing and individualization of radiation therapy on a genetic basis.     

Scedosporium apiospermum complex in cystic fibrosis; should we treat?

Species of the Scedosporium apiospermum complex are the second most frequent filamentous fungi after Aspergillus fumigatus that can be found in cystic fibrosis (CF). Mixed colonisation by S. apiospermum complex and A. fumigatus is also quite common . In this study we summarise all CF patients who were colonised by S. apiospermum complex during their childhood and we present two CF patients who were treated as fungal bronchitis due to S. apiospermum complex. The medical records of 400 CF patients were reviewed in order to identify those with positive respiratory cultures for S. apiospermum complex. Scedosporium apiospermum complex was isolated in 10 CF patients and six of them had more than two positive sputum cultures during the study period. By the time of first isolation, the median age was 14.5 years, the median BMI was 19.41 kg/m², the median predicted FEV₁% was 78.65% and six patients had a history of A. fumigatus isolation. Two patients presented symptoms of infection while they were colonised by S. apiospermum complex. A rapid remission of their symptoms was observed only when antifungal therapy was administered. Antifungal treatment should be considered in CF patients who present symptoms of infection not responding to antibacterial therapy and S. apiospermum complex is persistently growing in sputum cultures.     

Clinical significance of the ratio between the alpha 2 plasmin inhibitor–plasmin complex and the thrombin–antithrombin complex in advanced non-small cell lung cancer

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin–antithrombin complex (TAT), and plasmin-α2–plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.     

The diverse and complex roles of NF-κB subunits in cancer

It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.     

miRNAs in multiple myeloma – a survival relevant complex regulator of gene expression

Purpose

microRNAs regulate gene-expression in biological and pathophysiological processes, including multiple myeloma. Here we address i) What are the number and magnitude of changes in miRNA-expression between normal plasma cells and myeloma- or MGUS-samples, and the latter two? ii) What is the biological relevance and how does miRNA-expression impact on gene-expression? iii) Is there a prognostic significance, and what is its background?

Experimental design

Ninety-two purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line-samples were investigated using miChip-arrays interrogating 559 human miRNAs. Impact on gene-expression was assessed by Affymetrix DNA-microarrays in two cohorts of myeloma patients (n = 677); chromosomal aberrations were assessed by iFISH, survival for 592 patients undergoing up-front high-dose chemotherapy.

Results

Compared to normal plasma cells, 67/559 miRNAs (12%) with fold changes of 4.6 to −3.1 are differentially expressed in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS and myeloma. Expression of miRNAs is associated with proliferation, chromosomal aberrations, tumor mass, and gene expression-based risk-scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free and overall survival, as do respective target-gene signatures.

Conclusions

The myeloma-miRNome confers a pattern of small changes of individual miRNAs impacting on gene-expression, biological functions, and survival.     

Celecoxib up-regulates expression of■chain of TIL receptor complex in human cervical cancer

Tumor-infiltrating lymphocytes (TIL) were once considered as the effector cells in the immune attack against cancer.However,TIL had not been shown significant tumor cytolytic activity in vitro.This was later found to be due to down-regulation of theζchain of T cell receptor complex. Withoutζchain, signal transduction necessary for T cell activation would not occur. This is one of the reasons why tumor cells could evade immune surveillance of the host.A study by Ferrandina et al.from University of Rome has made clear the mechanism of tumor-induced down regulation ofζchain and how to restore its expression (Clin Cancer Res 12:2055-2060,2006).The authors     

The complex interplay between autophagy and NF-κB signaling pathways in cancer cells

Tight regulation of both the NF-κB pathway and the autophagy process is necessary for maintenance of cellular homeostasis. Deregulation of both pathways is frequently observed in cancer cells and is associated with tumorigenesis and tumor cell resistance to cancer therapies. Autophagy is involved in several cellular functions regulated by NF-κB including cell survival, differentiation, senescence, inflammation, and immunity. On a molecular level, autophagy and NF-κB share common upstream signals and regulators and can control each other through positive or negative feedback loops, thus ensuring homeostatic responses. Here, we summarize and discuss the most recent discoveries that shed new light on the complex interplay between autophagy and NF-κB signaling pathways; this certainly has functional relevance in tumorigenesis and tumor responses to therapy.     

The topoisomerase II–Hsp90 complex: A new chemotherapeutic target?

The modulation of DNA topology by topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and has thus become a highly attractive target for chemotherapeutic drugs. However, these drugs are highly toxic, and so new approaches are required. One such strategy is to target topoisomerase II-interacting proteins. Here we report the identification of potential topoisomerase II-associated proteins using immunoprecipitation, followed by 1-D and 2-D gel electrophoresis and MALDI-TOF mass spectrometry. A total of 23 proteins were identified and, of these, 17 were further validated as topoisomerase IIalpha-associated proteins by coimmunoprecipitation and Western blot. Six of the interacting proteins were cellular chaperones, including 3 members of the heat shock protein-90 (Hsp90) family, and so the effect of Hsp90 modulation on the antitumor activity of topoisomerase II drugs was tested using the sulforhodamine B assay, clonogenic assays and a xenograft model. The Hsp90 inhibitors geldanamycin, 17-AAG (17-allylamino-17-demethoxygeldanamycin) and radicicol significantly enhanced the activity of the topoisomerase II poisons etoposide and mitoxantrone in vitro and in vivo. Thus, our method of identifying topoisomerase II-interacting proteins appears to be effective, and at least 1 novel topoisomerase IIalpha-associated protein, Hsp90, may represent a valid drug target in the context of topoisomerase II-directed chemotherapy.     

Spindle cell carcinoma of the breast as complex cystic lesion： a case report

Spindle cell carcinoma of the breast is a rare tumor. This tumor can proliferate rapidly and cause cystic changes because of internal tissue necrosis. We evaluated a 54-year-old woman with right breast lump. Mammography showed a category four mass with a diameter of 2.5 cm. Ultrasonography（US） revealed a complex cystic lesion, and fine-needle aspiration（FNA） cytology demonstrated bloody fluid and malignant cells. Partial breast resection and sentinel lymph node biopsy were performed. Immunohistology revealed spindle cells with positive results for cytokeratin（AE1/AE3） and vimentin, partially positive results for s-100, and negative results for desmin and α-actin. The pathological stage was IIA, and biochemical characterization showed that the tumor was triple negative. Six courses of FEC-100 chemotherapy（5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2） were administered. Radiotherapy was performed. This case is discussed with reference to the literature.     

Nipple discharge after nipple-sparing mastectomy: should the areola complex always be removed?

Nipple discharge (ND) is a common symptom with a reported incidence of 2% to 5% of patients referred to breast cancer clinics. Approximately 90% of ND is of benign etiology. An underlying carcinoma is present with a rate of 6% to 21%. This is more frequent if it is associated with clinical or radiologic abnormality. ND after nipple-sparing mastectomy (NSM) is a rare event as the whole retroareolar glandular tissue is usually completely removed with mastectomy. ND is otherwise possible if a small amount of tissue is accidentally left by the surgeon or with the aim of reducing the risk of the nipple-areola complex (NAC) necrosis. This condition can be of concern as it may imply a local recurrence and therefore implicate NAC removal. Herein we report a case of a ND in an NSM in which only a selective duct excision allowed NAC preservation.     

The E-cadherin–catenin complex in tumour metastasis: structure,function and regulation

E-cadherin and the associated catenin complex have been recognised as performing a key role in cell adhesion. Loss of cell adhesion is seen as a key step in the cascade leading to tumour metastasis. The ability of both extra- and intracellular factors to regulate E-cadherin-mediated cell adhesion in physiological processes has provided insight into both the interactions of the E-cadherin–catenin complex, and possible mechanisms utilised by tumours in the process of metastasis. The interaction of the E-cadherin–catenin complex with various regulating factors, their effect on cell signalling pathways, and the relationship with the metastatic potential of tumours are reviewed.     

Therapeutic targeting of the focal adhesion complex prevents oncogenic TGF-β signaling and metastasis

Introduction  

Mammary tumorigenesis is associated with the increased expression of several proteins in the focal adhesion complex, including focal adhesion kinase (FAK) and various integrins. Aberrant expression of these molecules occurs concomitant with the conversion of TGF-β function from a tumor suppressor to a tumor promoter. We previously showed that interaction between β₃ integrin and TβR-II facilitates TGF-β-mediated oncogenic signaling, epithelial-mesenchymal transition (EMT), and metastasis. However, the molecular mechanisms by which the focal adhesion complex contributes to β₃ integrin:TβR-II signaling and the oncogenic conversion of TGF-β remain poorly understood.     

Laparoscopic glissonean approach: Making complex something easy or making suitable the unsuitable?

BackgroundThe use of laparoscopic glissonean approach has many potential benefits such as shorter operative times, lower blood loss with low morbidity.MethodsThe aim with this study was to perform an evaluation of 12 years of our experience with laparoscopic glissonean approach in liver surgery, from a technical standpoint using a prospective database. Anatomical laparoscopic liver resections using hilar dissection and non-anatomical resections were excluded from this study.Results327 patients (170 females and 157 males) with mean age of 56 years were included. 196 (60%) of procedures were major resections. 65% of procedures were performed in the last 5 years. 208 patients were operated on for secondary lesions. In 38 patients the liver was cirrhotic. Morbidity was 37.3% and 90-day mortality occurred in 2 patients (0.6%). Blood transfusion was necessary in 10.7% of patients. Median hospital stay was 4 days.ConclusionsLaparoscopic glissonean approach is a safe and feasible technique. It may be preferred in some clinical situations as it is associated with shorter operative times, lower blood loss, and low morbidity. It is superior to standard laparoscopic hepatectomy when an anatomical resection, especially if a segment or section is to be removed. However, application of this technique requires accurate preoperative tumor localization, identification of potential anatomic pedicle variations, as well as surgeon expertise.     

Sonodynamically induced apoptosis and active oxygen generation by gallium–porphyrin complex, ATX-70

In this study, we investigated the induction of apoptosis by ultrasound in the presence of the photochemically active gallium–porphyrin complex, 7,12-bis(1-decyloxyethyl)-Ga(III)-3,8,13,17-tetramethyl-porphyrin 2,18-dipropionyl diaspartic acid (ATX-70). HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of ATX-70, and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Cells treated with 80 μM ATX-70 and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound or ATX-70 alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and ATX-70 but not in cells treated with ultrasound or ATX-70 alone. In addition, the combination of ATX-70 and the same acoustical arrangement of ultrasound substantially enhanced nitroxide generation by the cells. Sonodynamically induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. These results indicate that the combination of ultrasound and ATX-70 induces apoptosis in HL-60 cells. The significant reduction in sonodynamically induced apoptosis, nitroxide generation, and caspase-3 activation by histidine suggests that active species such as singlet oxygen are important in the sonodynamic induction of apoptosis.     

β-Elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells

β-Elemene, an active component of herb medicine Curcuma wenyujin, has been shown to antagonize glioblastoma cells by inducing apoptosis. However, how β-elemene induces apoptosis of these cells remains unclear. In this study, we report that β-elemene disrupted the formation of the Hsp90/Raf-1 complex, a key step in maintaining the conformation stability of Raf-1, and caused deactivation of Raf-1 and inhibition of the ERK pathway, thereby leading to apoptosis of glioblastoma cells. Specifically, treatment of glioblastoma cell lines with β-elemene attenuated phosphorylation of multiple members of the kinase families in the Ras/Raf/MEK/ERK cascade, including Raf-1 and ERK as well as downstream signaling targets such as Bcl-2. These results suggest that the Hsp90/Raf-1 complex could be a promising molecular target for new drug development for the treatment of glioblastoma.