Classical Therapies Research Articles

Addressing the Complications of Ebola and Other Viral Hemorrhagic Fever Infections: Using Insights from Bacterial and Fungal Sepsis.

Research on Ebola virus (EBOV) has focused on preventing and controlling the infection using vaccines and antiviral therapies. Given the long-term challenge of the current epidemic and the likelihood of future outbreaks of viral hemorrhagic fevers caused by the filoviruses, including EBOV and Marburg virus, efforts should also focus on developing therapies to reduce the deadly complications of infection with these viruses [1,2]. There are striking similarities in the syndromes caused by bacterial and fungal sepsis [3–14] and by EBOV [15–27] (Table 1). Sepsis, defined as the systemic inflammatory response to infection, causes a spectrum of pathology ranging from mild, basic physiologic and laboratory derangements to shock, multiple organ failure, and death [3,7]. While the term “sepsis” is generally used in the context of bacterial and fungal infections, all microorganisms, including viruses, can cause sepsis. This Opinion argues that the wealth of knowledge about bacterial and fungal sepsis (herein referred to as “classical sepsis”) should be used to inform the development of adjunctive therapies to improve the outcome of EBOV and other viral hemorrhagic fevers. Table 1 Similarities between Severe and Fatal EBOV and Classical Sepsis.* Pathophysiology of Classical Sepsis and EBOV In classical sepsis, activation of innate immune pathways via pattern recognition receptors, such as the toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors, initiates systemic inflammation [29–31]. Maladaptive responses in sepsis cause excessive inflammation, endothelial dysfunction, coagulopathy, vascular leak, shock, and organ failure [11–13]. Analogous to the “cytokine storm” of classical sepsis, EBOV also causes systemic inflammation, endothelial dysfunction, coagulopathy, vascular leak, shock, and organ failure [17–25]. Fatal EBOV is associated with high levels of pro-inflammatory cytokines, chemokines, the anti-inflammatory cytokine IL-10, and nitric oxide [17,19,20]. Similar to classical sepsis, EBOV also causes immune suppression and a predisposition to secondary bacterial infections [11,15,23]. This latter complication has prompted the administration of empiric antibiotics to patients with EBOV [24–26]. It is possible that classical sepsis therapies may be beneficial in EBOV, in part because of their impact on the complications of secondary bacterial sepsis. The mechanisms underlying immune and endothelial cell dysfunction and organ failure in EBOV have yet to be unraveled. Infection of monocytes, macrophages, and dendritic cells leads to acute inflammation [16]. Early activation and subsequent massive apoptosis of T-lymphocytes is associated with fatal outcomes in EBOV [17,32]. The innate immune system has been implicated in the beneficial and harmful responses to EBOV [15,27,33,34]. The EBOV glycoprotein (GP) is a putative TLR4 agonist [27,35]. The shed surface GP of EBOV has been detected in the blood during infection; it activates macrophages and endothelial cells and induces endothelial cytotoxicity and permeability [27,36]. Finally, EBOV suppresses antiviral immunity by interfering with signaling via the innate immune receptor, RIG-I, and by interfering with type I interferon (IFN) production and signaling [28,37–40]. The resultant increased viral load may further exacerbate inflammation by activating innate immune pathways and by causing cytolysis.

Prognostic Significance of VEGF and bFGF in Egyptian CLL Patients

Though an impressive number of prognostic factors have been identified in chronic lymphocytic leukemia (CLL), which exhibits a high variability in its clinical presentation and course, many of them have not yet been applied in routine clinical practice. Among these factors are the angiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), previously reported as prognostic markers for disease progression. The objective of the present study was to assess the impact of serum VEGF and bFGF levels at diagnosis in Egyptian CLL patients and their relationship with disease prognostic parameters and patients' outcome, aiming to apply them in routine clinical practice. For this purpose, 45 newly diagnosed CLL patients and 25 healthy controls were recruited. VEGF and bFGF were found to be significantly higher in the CLL group when compared to the control group (P 320 pg/ml for VEGF and >145 pg/ml for bFGF was able to predict poor prognosis (treatment failure) in CLL patients with prognostic accuracies of 96.7% and 89.10% respectively. In conclusion: VEGF and bFGF represent powerful prognostic markers in B-CLL, partially because of the simplicity of obtaining their samples and their assays procedure, the reliability of their assessment besides being optimal targets for potential novel therapies in conjunction with classical therapies.

Abstract 5518: Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics

Abstract Treatment of advanced cancer, is an extremely challenging proposition. Surgery is curative at early stages, but with substantial complications. Molecular treatments in early disease are of questionable benefit, coupled with the lack of therapeutic options in advanced disease, make treatment extremely challenging. Early cancers evolve through many somatic mutations involving many selective processes, induced in part by classical drug therapies themselves initiating drug resistance. Genetic cancers studies show extensive single missense mutations, copy number variations, splicing variants, genetic rearrangements and short DNA alterations in a large number of genes. However, physical agent therapies are immune to genetic alterations, a targeting the cancer cell and adjacent cells. By investigating cell surface markers that are correlated with disease progression, we have coupled bio-affinity agents (antibody, ligand, aptamer) to functionalized carbon nanoparticles and developed a platform of delivering highly-localized “energy” in the immediate proximity to the cells causing significant cellular damage. Similarly, these agents can be simultaneously used as imaging agents, creates a theranostic treatment agent. We have used papillary thyroid (PTC) and prostate cancer (CaP) cancer cells and selectively targeted THSR and PSMA, respectively in our models. Using a 2W laser light for 30 seconds, we are able to achieve near 100% cell killing of targeted cells, whereas receptor-null cells remain unharmed. Electron microscopy was used as a direct analysis to answer the mechanistic question of cell necrosis and cell death that cannot be approached via light microscopy. Altogether these results suggest that significant and specific cell killing can be achieved with small amounts of power over short periods of time. In conclusion, whereas in the past, simultaneous multiple drugs therapies have been limited by systemic toxicities, this approach represents a single delivery platform that can carry several small molecule drugs, in conjunction with new genetic modalities, in a targeted fashion with the added benefit of self-imaging so as to document successful targeting. Citation Format: Idit Dotan, Philip J.R. Roche, Elliot Mitmaker, Mark A. Trifiro, Miltiadis Paliouras. Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2015-5518

TERAPIE CLASICĂ MODIFICATOARE A BOLII DE BAZĂ SAU TERAPIE BIOLOGICĂ ÎN POLIARTRITA REUMATOIDĂ?

Objectives. The purpose of this study is the evaluation of a group of patients suffering from rheumatoid arthritis depending on the administered treatment, classical remissive therapy or biological therapy. Materials and methods. We have performed a retrospective study on a group of 214 patients diagnosed with rheumatoid arthitis, admitted in the Internal Medicine and Rheumatology Clinic of „Dr. I. Cantacuzino“ Clinical Hospital Bucharest, 92 of whom were being administered biological therapy (etanercept, infliximab, adalimumab or rituximab) along with classical remissive therapies (methotrexate, leflunomide, sulfasalazine), and 122 of whom were only being administered classical treatment. We have studied and supervised the influence of these therapies on disease evolution, together with paying attention to several other health risks present in rheumatoid arthritis patients (cardiovascular risk, osteoporosis, joint replacement surgery, neoplasms). Results. In the studied group, the seropositive disease forms predominated (72%), in stages 2 and 3, the average patient age being 59.29±11.52 years. Systemic manifestations were present in patients who underwent biological therapy, presented seropositive disease forms, as well as a more aggresive evolution and a more decreased BMI. Female patients more frequently presented ischemic heart disease, dyslipidemia and increased cholesterol levels, thus comprising multiple cardiovascular risk factors as well as associated cardiovascular pathology. Patients treated with biological therapy have presented a significantly lower incidence of ischemic stroke as well as slightly decreased cholesterol levels, data which correlate with specialty literature. Treatment using statins was more frequently used in these cases. Although statistically unsignificant, the most decreased cholesterol levels were recorded in patients treated with etanercept. Smokers presented a weaker response to biological therapy as compared to non-smokers. Osteoporosis was more frequent in the group of patients treated with classical remissive therapy as well as in those with an increased disease activity, evaluated through the DAS 28 score and increased inflammation markers. DAS 28 was decreased in patients treated with biological treatment (infliximab, adalimumab, rituximab), and those in the third stage of disease, probably because of the more aggeresive treatement administered in these situations. Conclusions. Biological therapy has positively influenced disease evolution, patients presenting decreased values for inflammation markers as well as disease activity, evaluated using the DAS 28 score, in comparison with patients treated with classical remissive therapy. Cholesterol levels were lower in the group treated with biological therapy, as patients underwent statin treatment more frequently, thus presenting a reduced incidence of stroke. Moreover, osteoporosis was less frequent in the group treated with biological agents. These biological therapies did not influence the number of viral hepatitis infections, but in some cases have determined the reactivation of a series of tuberculosis infections. Neoplasms have not presented a significantly increased incidence in the group treated with biological therapy. Adverse effects of biological treatment will be further studied, but the beneficial effect on disease evolution as well as other disease-associated risks is certain.

Role of Nutraceuticals in Hypolipidemic Therapy.

Nutraceuticals are food components or active ingredients present in foods and used in therapy. This article analyzes the characteristics of the molecules with a lipid-lowering effect. The different nutraceuticals may have different mechanisms of action: inhibition of cholesterol synthesis primarily through action on the enzyme HMG-CoA reductase (policosanol, polyphenols, garlic and, above all, red yeast rice), increase in LDL receptor activity (berberine), reduction of intestinal cholesterol absorption (garlic, plant sterols, probiotics), and also the ability to interfere with bile metabolism (probiotics, guggul). Based on the different mechanisms of action, some nutraceuticals are then able to enhance the action of statins. Nutraceuticals are often used without relevant evidence: mechanisms of action are not clearly confirmed; most of clinical data are derived from small, uncontrolled studies, and finally, except for fermented red rice, there are no clinical trials which may document the relationship between these interventions and the reduction of clinical events. Therefore, among all nutraceuticals, it is necessary to extrapolate those having a really documentable efficacy. However, these kinds of treatments are usually well-tolerated by patients. Overall, subjects with a middle or low cardiovascular risk are the best indication of nutraceuticals, but they may also be useful for patients experiencing side effects during classical therapies. Finally, in consideration of the additive effect of some nutraceuticals, a combination therapy with classical drugs may improve the achievement of clinical targets. Thus, nutraceuticals may be a helpful alternative in hypolipidemic treatment and, if properly used, might represent a valid strategy of cardiovascular prevention.

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma

High pulmonary eosinophil counts are associated with asthma symptoms and severity. Bronchial epithelial cells (BECs) produce CC chemokines, notably CCL26 (eotaxin-3), which recruits and activates eosinophils from asthmatic patients. This suggests that CCL26 production by BECs might be involved in persistent eosinophilia in patients with severe asthma despite treatment with high corticosteroid doses. We sought to determine whether CCL26 levels correlate with eosinophilia and asthma severity. Human CC chemokine expression was assessed by means of quantitative PCR or a quantitative PCR array in vehicle- or IL-13-treated BECs. CCL26 was quantitated by means of ELISA. Immunohistochemistry analyses of CCL26 and major basic protein were done on bronchial biopsy specimens. IL-13 selectively induced CCL26 expression by BECs. This increase was time-dependent and more prominent in BECs from patients with severe eosinophilic asthma. CCL26 levels measured in supernatants of IL-13-stimulated BECs also increased with asthma severity as follows: patients with severe eosinophilic asthma > patients with mild asthma ≈ healthy subjects. Immunohistochemistry analyses of bronchial biopsy specimens confirmed increased levels of CCL26 in the epithelium of patients with mild and those with severe eosinophilic asthma. Tissue eosinophil counts did not correlate with CCL26 staining. However, sputum CCL26 levels significantly correlated with sputum eosinophil counts (P < .0001), suggesting that CCL26 participates in the movement of eosinophils from the tissues to the airway lumen. These results show a relation between CCL26 production by IL-13-stimulated BECs, sputum eosinophil counts, and asthma severity. They also suggest a role for CCL26 in the sustained inflammation observed in patients with severe eosinophilic asthma and reveal CCL26 as a potential target for treating patients with eosinophilic asthma that are refractory to classic therapies.

Parathyroid carcinoma: Challenges in diagnosis and treatment

Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (>1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed.

Apoptotic cell clearance and its role in the origin and resolution of chronic inflammation.

Apoptotic cell clearance and its role in the origin and resolution of chronic inflammation.

Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options.

During the last years increasing evidence implies that human cytomegalovirus (CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.

What Is New in Systemic Lupus Erythematosus

Systemic lupus erythematosus is a heterogeneous rheumatic systemic disease with extremely varied clinical manifestations and a diverse pathogenesis, as illustrated in this review on the most relevant new knowledge related to the disease. Topics such as anemia, pathogenesis, cardiovascular risk assessment, antiphospholipid syndrome, prediction of damage and recent advances in treatment, including tolerogenic and biological agents, are discussed. Relevant contributions regarding classical therapies such as corticosteroid and antimalarials and their optimal use, as well as the roll of vitamin D, are also referred.

Prodigiosin isolated from cell wall of Serratia marcescens alters expression of apoptosis-related genes and increases apoptosis in colorectal cancer cells.

Colorectal cancer remains often refractory to classic therapies. In consequence, the search for new anti-tumor agents with minimal toxicity is of particular interest in colon cancer treatment. Prodigiosin as a secondary metabolite of Serratia marcescens induces apoptosis in various kinds of cancer cells with low toxicity on normal cells. In the present study, we evaluated the effect of prodigiosin on proliferation and expression of apoptotic-related genes in HT-29 cells. Malignant cells were treated to various concentrations of prodigiosin and proliferation rate, survivin, Bcl-2, Bax and Bad mRNA levels, caspase 3 activation and apoptosis were evaluated by different cellular and molecular techniques. Treatment of cells with increasing concentration of prodigiosin decreased significantly cell proliferation in a dose- and time-dependent manner. Following 48-h treatment, growth rate was measured to be 77±6.8, 41.3±3.1 and 46±6.3% for 100, 400 and 600nM prodigiosin, respectively, compared to untreated cells. This molecule induced 61.7, 90 and 89% decrease in survivin mRNA level as well as 1.9-, 2.8- and 2.2-fold increase in caspase 3 activation for indicated concentrations of prodigiosin, respectively. The level of Bcl-2 mRNA was inversely proportional to Bax and Bad mRNA levels. Low mRNA levels of Bcl-2 combined with high levels of Bax and Bad mRNAs were correlated to higher apoptosis rate in treated cells. Our data suggest that prodigiosin-induced apoptosis may ascribe to Bcl-2 and survivin inhibition in HT-29 cells and these genes may provide promising molecular targets of prodigiosin. Collectively, prodigiosin may have a great potential for colorectal cancer-directed therapy.

Lo mejor del año en lupus eritematoso sistémico

Systemic lupus erythematosus is a heterogeneous rheumatic systemic disease with extremely varied clinical manifestations and a diverse pathogenesis, as illustrated in this review on the most relevant new knowledge related to the disease. Topics such as anemia, pathogenesis, cardiovascular risk assessment, antiphospholipid syndrome, prediction of damage and recent advances in treatment, including tolerogenic and biological agents, are discussed. Relevant contributions regarding classical therapies such as corticosteroid and antimalarials and their optimal use, as well as the roll of vitamin D, are also referred.

Copper Signaling Axis as a Target for Prostate Cancer Therapeutics

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Decade in review--arrhythmias: Cardiac fibrillation--challenges and evolving solutions.

Cardiac rhythm disorders, or 'arrhythmias', are major sources of morbidity and mortality, and have been challenging to treat because classic pharmacological therapies are often ineffective and sometimes dangerous. In the past decade, groundbreaking developments have revolutionized the management of arrhythmias and prepared the groundwork for new advances in the future.

Safety of classic and biologic systemic therapies for the treatment of psoriasis in elderly: an observational study from national BIOBADADERM registry.

Psoriasis patients over 65 years-old (elderly) constitute a growing group, underrepresented in clinical trials, and likely to be more prone to adverse events. To describe safety of systemic psoriasis therapy in patients over 65 years-old compared to younger patients. Patients registered in Biobadaderm, a Spanish national registry of psoriasis patients treated with systemic therapy, were grouped in elderly (≥ 65 years old) and younger patients. Rates of adverse events were described by severity and type, and the risks compared in both groups, taking into account exposure to classic or biologic drugs, using Cox regression. 175 (9.8%) of 1793 patients were elderly. Overall risk of adverse events was not higher in elderly (drug group adjusted HR 1.09 (95%CI: 0.93-1.3)). Serious adverse events were more common in elderly (drug group adjusted HR 3.2 (95%CI: 2.0-5.1)). Age adjusted HR of all adverse events was lower for patients exposed to biologics compared to classic drugs in the whole sample (HR 0.7 (95%CI: 0.6-0.7)). Age did not seem to modify the effect of therapy (biologic vs. classic) in the risk of adverse events (likelihood ratio test for interaction, p = 0.12 for all adverse events, p = 0-09 for serious adverse events). Serious adverse events are more common in elderly patients, although they may be related to other variants that are associated with this age group and not due to the treatment itself. Use of biologics was associated with lower risk of adverse events in the whole group. We found no differences in this association between young and elderly. These results are reassuring, although uncontrolled confounding could not be excluded as an explanation for these findings, and the power of the study to detect differences was low.

Systems pharmacology dissection of multi-scale mechanisms of action for herbal medicines in stroke treatment and prevention.

Annually, tens of millions of first-ever strokes occur in the world; however, currently there is lack of effective and widely applicable pharmacological treatments for stroke patients. Herbal medicines, characterized as multi-constituent, multi-target and multi-effect, have been acknowledged with conspicuous effects in treating stroke, and attract extensive interest of researchers although the mechanism of action is yet unclear. In this work, we introduce an innovative systems-pharmacology method that combines pharmacokinetic prescreening, target fishing and network analysis to decipher the mechanisms of action of 10 herbal medicines like Salvia miltiorrhizae, Ginkgo biloba and Ephedrae herba which are efficient in stroke treatment and prevention. Our systematic analysis results display that, in these anti-stroke herbal medicines, 168 out of 1285 constituents with the favorable pharmacokinetic profiles might be implicated in stroke therapy, and the systematic use of these compounds probably acts through multiple mechanisms to synergistically benefit patients with stroke, which can roughly be classified as preventing ischemic inflammatory response, scavenging free radicals and inhibiting neuronal apoptosis against ischemic cerebral damage, as well as exhibiting lipid-lowering, anti-diabetic, anti-thrombotic and antiplatelet effects to decrease recurrent strokes. Relying on systems biology-based analysis, we speculate that herbal medicines, being characterized as the classical combination therapies, might be not only engaged in multiple mechanisms of action to synergistically improve the stroke outcomes, but also might be participated in reducing the risk factors for recurrent strokes.

Dynamic changes in the numbers of different subsets of peripheral blood NK cells in patients with systemic lupus erythematosus following classic therapy.

Imbalance of natural killer (NK) cells is associated with the development of systemic lupus erythematosus (SLE). However, little is known about the dynamic changes on NK cells following therapy. This study aimed at examining the impact of classic therapies on the numbers of different subsets of NK cells in new-onset SLE patients. The numbers of different subsets of peripheral blood NK cells in 24 new-onset SLE patients before, 4 and 12weeks post the classic therapies, and 7 healthy controls were determined by flow cytometry. The potential correlation between the numbers of NK cells and the values of clinical measures was analyzed. In comparison with that before treatment, the numbers of NK, NKG2C+, and KIR2DL3+ NK cells were significantly increased while the numbers of NKp46+ and NKG2A + NK cells significantly decreased at 4 and/or 12weeks post the treatment only in the drug well-responding patients, but not in those poor responders (P < 0.05 for all). The numbers of NKG2C + NK cells were correlated positively with the levels of serum C3 while the numbers of KIR2DL3+ NK cells were correlated negatively with the scores of SLEDAI in these patients at 4weeks post the treatment. The classic therapies modulated the numbers of some subsets of NK cells in drug well-responding SLE patients. The changes in the numbers of some subsets of NK cells may serve as biomarkers for evaluating the therapeutic responses of SLE.

Abdominal and pelvic complications of nonoperative oncologic therapy.

Oncologic patients are treated with a combination of chemotherapy, radiation therapy, and surgery. Advances in therapeutic options have greatly improved the survival of patients with cancer. Examples of these advances are newer chemotherapeutic agents that target the cell receptors and advanced radiation therapy delivery systems. It is imperative that radiologists be aware of the variety of imaging findings seen after therapy in patients with cancer. Complications may occur with classic cytotoxic therapies (eg, 5-fluorouracil), usually at higher or prolonged doses or when administered to radiosensitive areas. Newer targeted systemic agents, such as bevacizumab and imatinib, have associated characteristic toxicities because their effects on cells do not depend on dose. Radiation may induce early and late effects in local normal tissues that may be seen at imaging. Imaging findings after chemotherapy include fatty liver, pseudocirrhosis, hepatic veno-occlusive disease, and splenic rupture. Complications of radiation therapy include large and small bowel strictures and radiation-induced hepatitis and tumors. Awareness of the various therapeutic options and knowledge of the spectrum of posttherapeutic complications allows radiologists to provide a comprehensive report that may impact patient management.

Inhibition of HDAC increases the senescence induced by natural polyphenols in glioma cells.

Cellular senescence is an irreversible block of cellular division, and induction of senescence is being considered for treatment of many cancer types, mainly those resistant to classical pro-apoptotic therapies. Resveratrol (Rsv) and quercetin (Quer), two natural polyphenols, are able to induce senescence in different cancer models, including gliomas, the most common and aggressive primary brain tumor. These polyphenols modulate the activity of several proteins involved in cell growth and death in cancer cells, including histone deacetylases (HDAC), but the role of HDAC in senescence induced by Rsv and Quer is unclear. The HDAC inhibitor sodium butyrate (NaB) potentiated the pro-senescent effect of Rsv and Quer in human and rat glioma cell lines but not in normal rat astrocytes. Furthermore, the increment of Quer-induced senescence by NaB was accompanied by an increase of reactive oxygen species levels and an increment of the number of cells with nuclear abnormalities. Altogether, these data support a positive role of HDAC inhibition on the senescence induced by these polyphenols, and therefore co-treatment of HDAC inhibitors and polyphenols emerges as a potential alternative for gliomas.

The side population of ovarian cancer cells defines a heterogeneous compartment exhibiting stem cell characteristics.

Cancer stem cells (CSC) are believed to be involved in tumor evasion of classical antitumor therapies and have thus become an attractive target for further improvement of anticancer strategies. However, the existence and identity of CSC are still a matter of controversy. In a systematic screen of 13 ovarian cancer cell lines we show that cells with stem cell properties are reliably detectable as a minor population, characterized by ABC transporter expression resulting in the side population (SP) phenotype. In different cell lines, either ABCG2 or ABCB1 was found to be responsible for this effect. Purified SP cells featured virtually all characteristics of bona fide CSC, including clonogenicity, asymmetric division and high tumorigenicity in vivo. Using in-depth phenotyping by multicolor flow cytometry, we found that among the investigated ovarian cancer cell lines the SP compartment exhibits tremendous heterogeneity and is composed of multiple phenotypically distinct subpopulations. Thus, our study confirms previous results showing that CSC are contained within the SP. However, the exact identity of the CSC is still disguised by the high complexity of the CSC-containing compartment. Further functional studies are needed to determine whether a single cellular subset can unambiguously be defined as CSC or whether multiple stem cell-like cells with different properties coexist. Moreover, the observed heterogeneity may reflect a high level of plasticity and likely influences tumor progression, escape from immune-surveillance and development of resistance to anticancer therapies and should therefore be considered in the development of new treatment strategies.