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Xylella fastidiosa ( Xf ) is a quarantine plant pathogen capable of colonizing the xylem of a wide range of hosts. Currently, there is no cure able to eliminate the pathogen from a diseased plant, but several integrated strategies have been implemented for containing the spread of Xf . Nanotechnology represents an innovative strategy based on the possibility of maximizing the potential antibacterial activity by increasing the surface-to-volume ratio of nanoscale formulations. Nanoparticles based on chitosan and/or fosetyl-Al have shown different in vitro antibacterial efficacy against Xf subsp. fastidiosa ( Xff ) and pauca ( Xfp ). This work demonstrated the uptake of chitosan-coated fosetyl-Al nanocrystals (CH-nanoFos) by roots and their localization in the stems and leaves of Olea europaea plants. Additionally, the antibacterial activity of fosetyl-Al, nano-fosetyl, nano-chitosan, and CH-nanoFos was tested on Nicotiana tabacum cultivar SR1 (Petite Havana) inoculated with Xff, Xfp , or Xf subsp. multiplex ( Xfm ). The bacterial load was evaluated with qPCR, and the results showed that CH-nanoFos was the only treatment able to reduce the colonization of Xff, Xfm , and Xfp in tobacco plants. Additionally, the area under the disease progress curve, used to assess symptom development in tobacco plants inoculated with Xff, Xfm , and Xfp and treated with CH-nanoFos, showed a reduction in symptom development. Furthermore, the twitching assay and bacterial growth under microfluidic conditions confirmed the antibacterial activity of CH-nanoFos., Competing Interests: The author(s) declare no conflict of interest.

Essential oil-based pesticides, which contain antimicrobial and antioxidant molecules, have potential for use in sustainable agriculture. However, these compounds have limitations such as volatility, poor water solubility, and phytotoxicity. Nanoencapsulation, through processes like micro- and nanoemulsions, can enhance the stability and bioactivity of essential oils. In this study, thyme essential oil from supercritical carbon dioxide extraction was selected as a sustainable antimicrobial tool and nanoencapsulated in an oil-in-water emulsion system. The investigated protocol provided high-speed homogenisation in the presence of cellulose nanocrystals as stabilisers and calcium chloride as an ionic crosslinking agent. Thyme essential oil was characterised via GC-MS and UV-vis analysis, indicating rich content in phenols. The cellulose nanocrystal/essential oil ratio and calcium chloride concentration were varied to tune the nanoemulsions' physical-chemical stability, which was investigated via UV-vis, direct observation, dynamic light scattering, and Turbiscan analysis. Transmission electron microscopy confirmed the nanosized droplet formation. The nanoemulsion resulting from the addition of crosslinked nanocrystals was very stable over time at room temperature. It was evaluated for the first time on Pseudomonas savastanoi pv. savastanoi , the causal agent of olive knot disease. In vitro tests showed a synergistic effect of the formulation components, and in vivo tests on olive seedlings demonstrated reduced bacterial colonies without any phytotoxic effect. These findings suggest that crosslinked cellulose nanocrystal emulsions can enhance the stability and bioactivity of thyme essential oil, providing a new tool for crop protection.

Platinum-based anticancer drugs are common in chemotherapy, but problems such as systemic toxicity and acquired resistance of some tumors hamper their clinical applications and therapeutic efficacy. It is necessary to synthesize Pt-based drugs and explore strategies to reduce side effects and improve pharmacokinetic profiles. Photo-responsive chemotherapeutics have emerged as an alternative strategy against several cancers, as photoactivation offers spatial selectivity and fewer side effects. Here, we combine chemical synthesis and nanotechnology to create a multifunctional platinum drug delivery system based on the novel metal complex [Pt(ppy)(curc)] (ppy = deprotonated 2-phenylpyridine, curc = deprotonated curcumin)] embodying the naturally occurring bioactive molecule, curcumin. The ultrasonication method coupled with the layer-by-layer technology was employed to produce nanocolloids, which demonstrated a good biocompatibility, higher solubility in aqueous solution, stability, large drug loading, and good biological activity in comparison with the free drug. In vitro release experiments revealed that the polymeric nanoformulation is relatively stable under physiological conditions (pH = 7.4 and 37 °C) but sensitive to acidic environments (pH = 5.6 and 37 °C) which would trigger the release of the loaded drug. Our approach modifies the bioavailability of this Pt-based drug increasing its therapeutic action in terms of both cytotoxic and anti-metastasis effects., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Quarantine pathogens require the investigation of new tools for effective plant protection. In particular, research on sustainable agrochemicals is the actual challenge. Plant extracts, essential oils, and gels are natural sources of efficient biocides, such as aromatic secondary metabolites. Thymol is the major phenolic constituent of thyme and oregano essential oils, and it can inhibit many pathogenic microbes. Thymol nanoparticles were obtained through adsorption on CaCO 3 nanocrystals, exploiting their carrier action. High loading efficiency and capability were reached as verified through UV and TGA measurements. We report the first study of thymol effect on Xylella fastidiosa, conducing both fluorometric assay and in vitro inhibition assay. The first test confirmed the great antibacterial effect of this compound. Finally, an in vitro test revealed an interesting synergistic action of thymol and nanocarriers, suggesting the potential application of thymol-nanoparticles as effective biocides to control Xylella fastidiosa infection.

A novel double-open-cubane (NNCO) 6 Co 4 Cl 2 cluster with a Co 4 O 6 core was made available under aqua-ultrasonic open atmosphere conditions for the first time. The ultrasonic clusterization of the (3,5-dimethyl-1 H -pyrazol-1-yl)methanol (NNCOH) ligand with CoCl 2 ·6H 2 O salts in ethanol yielded a high-purity and high-yield cluster product. Energy-dispersive X-ray (EDX), Fourier transform infrared (FT-IR), and ultraviolet (UV)-visible techniques were used to elucidate the clusterization process. The double-open-Co 4 O 6 cubane structure of the (NNCO) 6 Co 4 Cl 2 cluster was solved by synchrotron single-crystal X-ray diffraction (SXRD) and supported by density functional theory (DFT) optimization and thermogravimetric/differential TG (TG/DTG) measurements; moreover, the DFT structural parameters correlated with the ones determined by SXRD. Molecular electrostatic potential (MEP), Mulliken atomic charge/natural population analysis (MAC/NPA), highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO), density of states (DOS), and GRD quantum analyses were computed at the DFT/B3LYP/6-311G(d,p) theory level. The thermal behavior of the cluster was characterized to support the formation of the Co 4 O 6 core as a stable final product. The catalytic property of the (NNCO) 6 Co 4 Cl 2 cluster was predestined for the oxidation process of 3,5-DTBC diol (3,5-di- tert -butylbenzene-1,2-diol) to 3,5-DTBQ dione (3,5-di- tert -butylcyclohexa-3,5-diene-1,2-dione)., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Given numerous publications and clinical trials regarding axillary management in breast cancer, we sought to summarize this complex literature to help clarify this field for clinicians. This systematic review focuses on the role of irradiation of the axillary nodes (locoregional nodal irradiation [LRNI]) in the management of the axilla in patients with early-stage breast cancer in various clinical settings., Methods: We searched MEDLINE and EMBASE databases, the Cochrane library, the proceedings of the ASCO, the ASTRO, the ESMO, the ESTRO, and the San Antonio Breast Cancer Symposium (2016-2019) meetings. The quality of the studies was assessed with design-specific tools. The study was registered in PROSPERO., Results: We included one systematic review, one individual patient data (IPD) meta-analysis, and five randomized controlled trials (RCTs). After axillary lymph node dissection (ALND), LRNI resulted in small benefits in breast cancer specific mortality, locoregional recurrence, and distant metastases-free survival but not overall survival. After a positive sentinel node biopsy (SLNB), LRNI may provide equivalent locoregional control and disease-free survival (DFS) compared to ALND with a lower risk of lymphedema. No randomized data is available for the neoadjuvant setting., Conclusions: The summary of the role of radiation, is relevant to radiation oncologists for choosing the correct cohort of patient requiring LRNI and to surgeons making clinical decisions regarding the timing and type of breast reconstruction offered to patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study aimed to evaluate the therapeutic efficacy of low-intensity visible light responsive nanocolloids of a Pt-based drug using a 2D and three-dimensional (3D) in vitro cancer cell model. Biocompatible and biodegradable polymeric nanocolloids, obtained using the ultrasonication method coupled with Layer by Layer technology, were characterized in terms of size (100 ± 20 nm), physical stability, drug loading (78%), and photoactivation through spectroscopy studies. The in vitro biological effects were assessed in terms of efficacy, apoptosis induction, and DNA-Pt adducts formation. Biological experiments were performed both in dark and under visible light irradiation conditions, exploiting the complex photochemical properties. The light-stimuli responsive nanoformulation gave a significant enhancement in drug bioactivity. This allowed us to achieve satisfying results by using nanomolar drug concentration (50 nM), which was ineffective in darkness condition. Furthermore, our nanocolloids were validated in 3D in vitro spheroids using confocal microscopy and cytofluorimetric assay to compare their behavior on culture in 2D monolayers. The obtained results confirmed that these nanocolloids are promising tools for delivering Pt-based drugs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Viviana Vergaro et al.)

Pomegranate peel extract is rich of interesting bioactive chemicals, principally phenolic compounds, which have shown antimicrobial, anticancer, and antioxidative properties. The aim of this work was to improve extract' bioactivity through the adsorption on calcium carbonate nanocrystals. Nanocrystals revealed as efficient tools for extract adsorption reaching 50% of loading efficiency. Controlled release of the contained metabolites under acidic pH has been found, as it was confirmed by quantitative assay and qualitative study through NMR analysis. Specific functionality of inorganic nanocarriers could be also tuned by biopolymeric coating. The resulting coated nanoformulations showed a great antimicrobial activity against B. cinerea fungus preventing strawberries disease better than a commercial fungicide. Furthermore, nanoformulations demonstrated a good antiproliferative activity in neuroblastoma and breast cancer cells carrying out a higher cytotoxic effect respect to free extract, confirming a crucial role of nanocarriers. Finally, pomegranate peel extract showed a very high radical scavenging ability, equal to ascorbic acid. Antioxidant activity, measured also in intracellular environment, highlighted a protective action of extract-adsorbed nanocrystals twice than free extract, providing a possible application for new nutraceutical formulations., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Francesca Baldassarre et al.)

Background and Aims: SARS-CoV-2-infected patients can experience long-lasting symptoms even after the resolution of the acute infection. This condition, defined as Long COVID, is now recognized as a public health priority and its negative impact on the quality of life of the patients could be more relevant in individuals with debilitating pathologies. We here evaluated the frequency of Long COVID in patients with inflammatory bowel diseases (IBD)., Methods: IBD patients afferent for scheduled visits to our tertiary referral center at the Tor Vergata University Hospital, Rome, were recruited from 7 September to 22 October 2021. During the visits, patients were investigated about previous COVID-19 infection and the possible development of Long COVID., Results: Fifty-three out of 528 IBD patients (10%) have had a SARS-CoV-2 infection. Of these, 21 patients (40%) developed Long COVID, and asthenia was the more frequent symptom as it occurred in nearly two-thirds of patients. Patients with Long COVID were more frequently females, while other clinical and demographic characteristics did not differ between patients with Long COVID and those without Long COVID. In particular, the IBD relapses occurred with the same frequency in the two groups., Conclusions: Long COVID appears to be common in IBD patients even though it does not influence the IBD course.

Motivation: Proteins are ubiquitous molecules whose function in biological processes is determined by their 3D structure. Experimental identification of a protein's structure can be time-consuming, prohibitively expensive and not always possible. Alternatively, protein folding can be modeled using computational methods, which however are not guaranteed to always produce optimal results. GraphQA is a graph-based method to estimate the quality of protein models, that possesses favorable properties such as representation learning, explicit modeling of both sequential and 3D structure, geometric invariance and computational efficiency., Results: GraphQA performs similarly to state-of-the-art methods despite using a relatively low number of input features. In addition, the graph network structure provides an improvement over the architecture used in ProQ4 operating on the same input features. Finally, the individual contributions of GraphQA components are carefully evaluated., Availability and Implementation: PyTorch implementation, datasets, experiments and link to an evaluation server are available through this GitHub repository: github.com/baldassarreFe/graphqa., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

Olive quick decline syndrome (OQDS) is a multifactorial disease affecting olive plants. The onset of this economically devastating disease has been associated with a Gram-negative plant pathogen called Xylella fastidiosa (Xf). Liquid chromatography separation coupled to high-resolution mass spectrometry detection is one the most widely applied technologies in metabolomics, as it provides a blend of rapid, sensitive, and selective qualitative and quantitative analyses with the ability to identify metabolites. The purpose of this work is the development of a global metabolomics mass spectrometry assay able to identify OQDS molecular markers that could discriminate between healthy (HP) and infected (OP) olive tree leaves. Results obtained via multivariate analysis through an HPLC-ESI HRMS platform (LTQ-Orbitrap from Thermo Scientific) show a clear separation between HP and OP samples. Among the differentially expressed metabolites, 18 different organic compounds highly expressed in the OP group were annotated; results obtained by this metabolomic approach could be used as a fast and reliable method for the biochemical characterization of OQDS and to develop targeted MS approaches for OQDS detection by foliage analysis.

Nanoparticle-based drug delivery systems for cancer therapy offer a great promising opportunity as they specifically target cancer cells, also increasing the bioavailability of anticancer drugs characterized by low water solubility. Platicur, [Pt(cur) (NH 3 ) 2 ](NO 3 ), is a cis -diamine-platinum(II) complex linked to curcumin. In this work, an ultrasonication method, coupled with layer by layer technology, allows us to obtain highly aqueous stable Platicur nanocolloids of about 100 nm. The visible light-activated Platicur nanocolloids showed an increased drug release and antitumor activity on HeLa cells, with respect to Platicur nanocolloids in darkness. This occurrence could give very interesting insight into selective activation of the nanodelivered Pt(II) complex and possible side-effect lowering. For the first time, the metabolic effects of Platicur nanocolloid photoactivation, in the HeLa cell line, have been investigated using an NMR-based metabolomics approach coupled with statistical multivariate data analysis. The reported results highlight specific metabolic differences between photoactivated and non-photoactivated Platicur NC-treated HeLa cancer cells.

Recently, there is a growing demand in sustainable phytopathogens control research. Nanotechnology provides several tools such as new pesticides formulations, antibacterial nanomaterials and smart delivery systems. Metal nano-oxides and different biopolymers have been exploited in order to develop nanopesticides which can offer a targeted solution minimizing side effects on environment and human health. This work proposed a nanotechnological approach to obtain a new formulation of systemic fungicide fosetyl-Al employing ultrasonication assisted production of water dispersible nanocrystals. Moreover, chitosan was applicated as a coating agent aiming a synergistic antimicrobial effect between biopolymer and fungicide. Fosetyl-Al nanocrystals have been characterized by morphological and physical-chemical analysis. Nanotoxicological investigation was carried out on human keratinocytes cells through cells viability test and ultrastructural analysis. In vitro planktonic growth, biofilm production and agar dilution assays have been conducted on two Xylella fastidiosa subspecies. Fosetyl-Al nanocrystals resulted very stable over time and less toxic respect to conventional formulation. Finally, chitosan-based fosetyl-Al nanocrystals showed an interesting antibacterial activity against Xylella fastidiosa subsp. pauca and Xylella fastidiosa subsp . fastidiosa ., Competing Interests: The authors declare no conflict of interest.

Although considered the gold standard in treatment of EBC, sentinel node biopsy still remains a debated issue. What to do in case of positive sentinel node and the need of intraoperative histological examination are the most topics under discussion. In this study we have retrospectively evaluate our case series of 359 sentinel node biopsy in the managing of breast cancer from January 2011 to December 2018, focusing on the TIC technique for performing intraoperative examination. It results in 12,8% "FALSE NEGATIVE" rate, in which only 4,2% in macrometastases, with an overall sensitivity of 68,4% (macrometastases: 86%; micrometastases: 11%), overall specificity of 98,7% and an overall accuracy of 89,7%. The intraoperative examination of SLN allows to reduce delayed surgery procedures and greater therapeutic safety in case of mastectomy. The TIC method can be considered valid, simple and rapid in identifying macrometastases, also allowing to avoid under-staging. The low sensitivity for micrometastases is not a limit, considering that recent evidence has drastically reduced the indications for ALND in these cases. Further ongoing trials and the possible validation of NOMOGRAMMS and SCORE are necessary to identify low risk cases in which to definitively omit the ALND and/or even the SLNB itself.

Chemical and biochemical functionalization of nanoparticles (NPs) can lead to an active cellular uptake enhancing their efficacy thanks to the targeted localization in tumors. In the present study calcium carbonate nano-crystals (CCNs), stabilized by an alcohol dehydration method, were successfully modified by grafting human serum albumin (HSA) on the surface to obtain a pure protein corona. Two types of CCNs were used: naked CaCO 3 and the (3-aminopropyl)triethoxysilane (APTES) modified CaCO 3 -NH 2 . The HSA conjugation with naked CCN and amino-functionalized CCN (CCN-NH 2 ) was established through the investigation of modification in size, zeta potential, and morphology by Transmission Electron Microscopy (TEM). The amount of HSA coating on the CCNs surface was assessed by spectrophotometry. Thermogravimetric analysis (TGA) and Differential scanning calorimetry (DSC) confirmed the grafting of APTES to the surface and successive adsorption of HSA. Furthermore, to evaluate the effect of protein complexation of CCNs on cellular behavior, bioavailability, and biological responses, three human model cancer cell lines, breast cancer (MCF7), cervical cancer (HeLa), and colon carcinoma (Caco-2) were selected to characterize the internalization kinetics, localization, and bio-interaction of the protein-enclosed CCNs. To monitor internalization of the various conjugates, chemical modification with fluorescein-isothiocyanate (FITC) was performed, and their stability over time was measured. Confocal microscopy was used to probe the uptake and confirm localization in the perinuclear region of the cancer cells. Flow cytometry assays confirmed that the bio-functionalization influence cellular uptake and the CCNs behavior depends on both cell line and surface features., Competing Interests: The authors declare no conflict of interest.

Owing to their nano-sized porous structure, CaCO₃ nanocrystals (CaCO₃NCs) hold the promise to be utilized as desired materials for encapsulating molecules which demonstrate wide promise in drug delivery. We evaluate the possibility to encapsulate and release NVP-BEZ235, a novel and potent dual PI3K/mTOR inhibitor that is currently in phase I/II clinical trials for advanced solid tumors, from the CaCO₃NCs. Its chemical nature shows some intrinsic limitations which induce to administer high doses leading to toxicity; to overcome these problems, here we proposed a strategy to enhance its intracellular penetration and its biological activity. Pristine CaCO₃ NCs biocompatibility, cell interactions and internalization in in vitro experiments on T-cell lymphoma line, were studied. Confocal microscopy was used to monitor NCs-cell interactions and cellular uptake. We have further investigated the interaction nature and release mechanism of drug loaded/released within/from the NCs using an alternative approach based on liquid chromatography coupled to mass spectrometry. Our approach provides a good loading efficiency, therefore this drug delivery system was validated for biological activity in T-cell lymphoma: the anti-proliferative test and western blot results are very interesting because the proposed nano-formulation has an efficiency higher than free drug at the same nominal concentration., Competing Interests: The authors declare no conflicts of interest.

Carbohydrate polimeric microcapsules were assembled using a LbL approach onto a CaCO 3 core. The microcapsules were used to delivery the anticancer drug cisplatin into HeLa and MCF-7 cancer cell lines. Drug encapsulation, measured by ICP spectroscopy, was around 50% of the charging solution. Fluorimetric measurements showed an efficient cellular uptake of polysacchardic microcapsules in both cell lines. The drug-loaded capsules demonstrated a better efficiency against cell viability than the free drug. Specifically, the amount of platinum reaching genomic DNA was measured, showing that encapsulation improves the nuclear delivery of the drug for both cell lines., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The growth of MoO 3 hierarchical plates was obtained by direct resistive heating of molybdenum foils at ambient pressure in the absence of any catalysts and templates. Plates synthesized after 60 min resistive heating typically grow in an single-crystalline orthorhombic structure that develop preferentially in the [001] direction, and are characterized by high resolution transmission electron microscopy, selected area diffraction pattern and Raman-scattering measurements. They are about 100-200 nm in thickness and a few tens of micrometers in length. As heating time proceeds to 80 min, plates of α-MoO 3 form a branched structure. A more attentive look shows that primary plates formed at until 60 min could serve as substrates for the subsequent growth of secondary belts. Moreover, a full electrochemical characterization of α-MoO 3 plates on platinum electrodes was done by cyclic voltammetric experiments, at pH 7 in phosphate buffer, to probe the activity of the proposed composite material as anode to methanol electro-oxidation. Reported results indicate that Pt MoO 3 modified electrodes are appropriate to develop new an amperometric non-enzymatic sensor for methanol as well as to make anodes suitable to be used in direct methanol fuel cells working at neutral pH.

Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm 3 ; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

In the past, treatment for patients with early-stage Hodgkin lymphoma consisted mainly of radiotherapy. Now, chemotherapy alone and chemoradiotherapy are treatment options. These guidelines aim to provide recommendations on the optimal management of early-stage Hodgkin lymphoma. We conducted a systematic review searching MEDLINE, EMBASE, the Cochrane Library and other literature sources from 2003 to 2015, and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Two authors independently reviewed and selected studies, and appraised the evidence quality. The document underwent internal and external review by content, methodology experts, a patient representative and clinicians in Ontario. We have issued recommendations for patients with classical Hodgkin lymphoma and with nodular lymphocyte predominant Hodgkin lymphoma; with favourable and unfavourable prognosis; and for the use of positron emission tomography to direct treatment. We have provided our interpretation of the evidence and considerations for implementation. Examples of recommendations are: 'Patients with early-stage classical Hodgkin lymphoma should not be treated with radiotherapy alone'; 'chemotherapy plus radiotherapy or chemotherapy alone are recommended treatment options for patients with early-stage non-bulky Hodgkin lymphoma'; 'The Working Group does not recommend the use of a negative interim positron emission tomography scan alone to identify patients with early-stage Hodgkin lymphoma for whom radiotherapy can be omitted without a reduction in progression-free survival'. Through the use of GRADE, recommendations were geared towards patient important outcomes and their strength reflected the available evidence and its interpretation from the patients' point of view., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The photodynamic activity occurring through the lysosome photo-damage is effective in terms of triggered synergic effects which can avoid chemo-resistance pathways. The potential photodynamic activity of two fluorescent lysosome-specific probes was studied providing their interaction with human serum albumin, demonstrating their in vitro generation of singlet oxygen and investigating the resulted photo-toxic effect in human cancer cells., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The new goal of anticancer agent research is the screening of natural origin drugs with lower systemic adverse effects than synthetic compounds. Here, we focus on curcumin, an important polyphenolic pigment classically used as spice in the Indian cuisine. The molecule has high pleiotropic activities including strong antioxidant and anti-inflammatory properties. However, its clinical potential is limited due its low solubility and bioavailability. We have developed a layer by layer functionalization of Fe3 O4 nanoparticles (nano-Fe3 O4 ) by coating biodegradable polyelectrolyte multilayers such as Dextran (DXS) and Poly(l-lysine) (PLL). Physico-chemical studies were performed to obtain a high upload of curcumin in Fe3 O4 nanoparticles. Nano-Fe3 O4 were then tested against an ovarian cancer cell line, SKOV-3, to demonstrate their therapeutic efficacy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Three fluorenone-derived two-photon fluorescent probes (TK) targeting the lysosomes (TK-Lyso) and mitochondria (TK-Mito1 and TK-Mito2) were synthesized by introducing different diphenylamine moieties into the fluorenone core. The TK dyes showed high biocompatibility and long-term retention, low cytotoxicity, large Stokes shift and good fluorescence quantum yield. The results of the present work disclose a class of organic dyes with potential wide applications as specific and efficient probes for lysosomes and mitochondria in the study of various biological processes.

Background: Selective imaging of lysosomes by fluorescence microscopy using specific fluorescent probes allows the study of biological processes and it is potentially useful also for diagnosis. Lysosomes are involved in numerous physiological processes, such as bone and tissue remodeling, plasma membrane repair, and cholesterol homeostasis, along with cell death and cell signaling. Despite the great number of dyes available today on the market, the search for new fluorescent dyes easily up-taken by cells, biocompatible and bearing bright and long-lasting fluorescence is still a priority., Methods: Two thiophene-based fluorescent dyes, TC1 and TC2, were synthetized as lysosome-specific probes., Results: The new dyes showed high selectivity for fluorescent staining and imaging of lysosomes and disclosed high photostability, low toxicity and pH insensitivity in the range 2-10., Conclusions: The TC dyes exhibited high co-localization coefficients (>95%) and moderate quantum yields. They showed high biocompatibility and long-term retention, important features for biological applications., General Significance: The results of the present work disclose a new class of organic dyes with potential wide applications as specific and efficient lysosome probes in the study of various biological processes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.

Polyelectrolyte multilayer (PEM) capsules engineered with active elements for targeting, labeling, sensing and delivery hold great promise for the controlled delivery of drugs and the development of new sensing platforms. PEM capsules composed of biodegradable polyelectrolytes are fabricated for intracellular delivery of encapsulated cargo (for example peptides, enzymes, DNA, and drugs) through gradual biodegradation of the shell components. PEM capsules with shells responsive to environmental or physical stimuli are exploited to control drug release. In the presence of appropriate triggers (e.g., pH variation or light irradiation) the pores of the multilayer shell are unlocked, leading to the controlled release of encapsulated cargos. By loading sensing elements in the capsules interior, PEM capsules sensitive to biological analytes, such as ions and metabolites, are assembled and used to detect analyte concentration changes in the surrounding environment. This Review aims to evaluate the current state of PEM capsules for drug delivery and sensing applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aims: Bortezomib (Velcade™, PS-341), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma. We created a provincial guideline for the use of bortezomib, in newly diagnosed individuals (both eligible and ineligible for transplant) and in individuals with relapsed or refractory multiple myeloma., Materials and Methods: A systematic review was conducted searching MEDLINE, EMBASE, the Cochrane Library and relevant meeting abstracts. Outcomes of interest were survival, disease control, response rate, response duration, quality of life and adverse effects. Members of the Cancer Care Ontario Hematology Disease Site Group (CCO HDSG), comprising physicians with content expertise, epidemiologists and consumers, developed a guideline through a systematic process that involved assessment of the best available evidence, consensus interpretation of the evidence and a validation process involving practitioners across the province., Results: The CCO HDSG recommends the use of bortezomib-based combinations in previously untreated patients with multiple myeloma who are candidates for autologous stem cell transplantation and in individuals who are ineligible for autologous stem cell transplantation. The group further recommends the use of bortezomib, alone or in combination, for patients with relapsed/refractory disease. The evidence did not establish a subgroup of patients with myeloma that should be uniquely targeted for therapy with bortezomib. Qualifying statements by the HDSG address alternative dosing options, the management of cytopenias and the prevention of toxicities, including herpes zoster reactivation., Conclusions: Bortezomib alone or in combination with other agents can be recommended for both previously untreated or relapsed/refractory patients with multiple myeloma. Guidelines for monitoring and reducing toxicity are provided., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Promising new drugs such as lenalidomide, an immunomodulatory agent, are available for the treatment of multiple myeloma. We describe the process of creating a provincial guideline for the use of lenalidomide, alone or in combination with other drugs, in relapsed, refractory, or newly diagnosed disease (including smoldering and symptomatic patients, and candidates and non-candidates for transplant) and in maintenance treatment (after transplant or non-transplant therapy); and for strategies to manage lenalidomide-related toxicities., Methods: Outcomes of interest included overall survival, event-free survival, progression-free survival, time to progression, time to next treatment, response rate, and incidence of serious toxicity. The medline, embase, and Cochrane Library databases, as well as meeting abstracts and the Web sites of relevant organizations, were systematically searched for relevant literature., Results: Recommendations were developed using the evidence from published studies and the clinical expertise of the working group and of the Cancer Care Ontario Hematology Disease Site Group., Conclusions: Lenalidomide in combination with dexamethasone can be recommended for both previously untreated and treated patients with multiple myeloma. Guidelines for the management of cytopenias, venous thromboembolism, and second primary malignancies are discussed.

Objectives: We set out to create a psychosocial oncology care framework and a set of relevant recommendations that can be used to improve the quality of comprehensive cancer care for Ontario patients and their families.meet the psychosocial health care needs of cancer patients and their families at both the provider and system levels., Data Sources and Methods: The adapte process and the practice guideline development cycle were used to adapt the 10 recommendations from the 2008 U.S. Institute of Medicine standard Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs into the psychosocial oncology care framework. In addition, the evidence contained in the original document was used, in combination with the expertise of the working group, to create a set of actionable recommendations. Refinement after formal external review was conducted., Data Extraction and Synthesis: The new framework consists of 8 defining domains. Of those 8 domains, 7 were adapted from recommendations in the source document; 1 new domain, to raise awareness about the need for psychosocial support of cancer patients and their families, was added. To ensure high-quality psychosocial care and services, 31 actionable recommendations were created. The document was submitted to an external review process. More than 70% of practitioners rated the quality of the advice document as high and reported that they would recommend its use., Conclusions: This advice document advocates for a multidisciplinary approach to cancer care in response to the distress experienced by cancer patients and their families. The recommendations will be useful in future to measure performance, quality of practice, and access to psychosocial services.

The efficient internalization of TGF-beta inhibitor-loaded polyelectrolyte capsules and particles is studied in two HCC cell lines. Two polyelectrolyte pairs (biocompatible but not degradable and biodegradable crosslinked with gluteraldehyde) are employed for coating. The capsules are characterized by SEM. LY is successfully loaded inside the core and embedded between polymer layers. MS is used to quantify the loading efficiency by comparing post-loading and core-loading methods, since both coated templates and hollow shells are used as carriers. CLSM confirms dissolution of the pre-formed multilayer upon enzymatic degradation as the method of release, and migration assays demonstrate a higher inhibition efficiency of TGF-beta in tailored biodegradable capsules compared to free LY administration., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this review we will report on recent advanced in polyelectrolyte capsules for targeted drug delivery (eg of growth factor inhibitor) against epatocarcinoma. Degradable polyelectrolyte multilayers capsules (PMCs) are of particular interest for cancer therapy since under physiological conditions they can be enzymatically degraded upon cell interaction. Small bioactive molecules such as TGF-Beta inhibitors can be incorporated inside them. Nano-to-microscale delivery systems can enhance efficacy at single cell level for targeted therapy. Layer-by-layer (LbL) self-assembled capsules are novel carriers maximizing drug administration and improving antimetastatic activity of TGF-Beta inhibitors in Hepatocellular Carcinoma (HCC).

The aim of this overview was to assess the utility of various imaging technologies (fluoroscopy, ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography) for the treatment planning of high dose rate brachytherapy for cervical cancer. Reviews and primary studies comparing different imaging technologies used during high dose rate brachytherapy for cervical cancer and published from 1988 to 2008 were sought by searching MEDLINE and EMBASE databases, the Cochrane Library, personal files and reference lists of identified studies, and by contacting experts. Study selection, study quality assessment and data extraction were carried out in duplicate. Twelve studies met the inclusion criteria. No systematic reviews or randomised controlled studies (RCTs) were located. The validity assessment revealed that the quality of the existing studies is very variable. This is the first systematic review in the area of imaging technologies for cervix brachytherapy. No RCTs have been located and it is possible that an RCT is not the optimal methodology to assess imaging technologies. However, in this area there is a need for more prospective studies and for studies that consider the expertise of the operators in their design. The studies found supported the use of three-dimensional imaging as opposed to the traditional two-dimensional imaging. However, apart from the effectiveness of visualising tumours and surrounding tissues, the utility of imaging technologies in clinical practice is determined by other contextual factors, such as their availability, accessibility and ease of use., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

In this review we will overview novel nanotechnological nanocarrier systems for cancer therapy focusing on recent development in polyelectrolyte capsules for targeted delivery of antineoplastic drugs against cancer cells. Biodegradable polyelectrolyte microcapsules (PMCs) are supramolecular assemblies of particular interest for therapeutic purposes, as they can be enzymatically degraded into viable cells, under physiological conditions. Incorporation of small bioactive molecules into nano-to-microscale delivery systems may increase drug's bioavailability and therapeutic efficacy at single cell level giving desirable targeted therapy. Layer-by-layer (LbL) self-assembled PMCs are efficient microcarriers that maximize drug's exposure enhancing antitumor activity of neoplastic drug in cancer cells. They can be envisaged as novel multifunctional carriers for resistant or relapsed patients or for reducing dose escalation in clinical settings., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Aims: Brachytherapy is a standard therapy for cervical cancer; it allows for the delivery of a high dose of radiation to the tumour while sparing the surrounding healthy tissues. With this document, the Brachytherapy Cervical Cancer Expert Working Group (BCCEWG) aimed to provide advice on organisational and technical aspects of the delivery of brachytherapy services in Ontario, Canada., Materials and Methods: We sought technical documents, practice guidelines and standards through an environmental scan of internet resources, an iterative search of the literature on MEDLINE and EMBASE, and a search of reference lists of included documents., Results: We identified 20 guidance documents authored by 10 organisations; 11 documents were identified through the environmental scan, five through the literature search and four from reference lists. The recommendations included in this document were developed by the BCCEWG through the selection and review of the evidence and informal consensus., Conclusions: These organisational recommendations aim to set the stage for high-quality delivery of brachytherapy for cervical cancer services in the province of Ontario, Canada. They address the characteristics of the practice setting, including facilities, equipment, delivery suite, imaging technologies, treatment planning and dosimetry; the practice team, including team members, roles, training, team caseload/volumes and qualifications; and the quality assurance domain, including documentation, audit, safety and quality control., (Copyright (c) 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Gossypiboma, i.e. a retained surgical sponge, is a serious and rare complication in surgical practice, most commonly occurring in abdominal procedures. Migration of retained surgical sponge is an unusual sequelae, particularly if occurring in tracheo-bronchial tree. Herein, we report a 35-year-old man who had had a retained surgical sponge forgotten during a radical thyroidectomy, and subsequently a trans-luminal migration of the gossypiboma which went through the trachea causing a sudden death of the patient. All the operators of the surgical team should keep in mind this terrible complication to avoid unpleasant consequences to patient and themselves., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

We describe the clinicopathological and morphological features of an unusual breast carcinoma classifiable as a lipid-rich variant of ductal invasive carcinoma, with a basal-type immunohistochemical profile. Basal-type breast cancers show no hormonal receptor expression, rarely over-express HER-2 but exhibit molecular high weight cytokeratins, EGFR and c-kit positivity. Special stains and histochemistry tests were used to elucidate the nature of vescicles in the neoplastic cells. Sudan IV was performed on formalin-fixed tissue. Commercially available antibodies tested were: ER, PgR, EGFR, HER2, c-kit, high molecular weight cytokeratins. Cytoplasmic lipids were highlighted as red-orange droplets on Sudan IV staining. As for immunohistochemistry, the tumor showed no reactivity to ER, PgR and HER2 (triple negative), and diffuse and strong positivity to high weight cytokeratins, EGFR and c-kit, such as a basal-type breast carcinoma. A basaloid phenotype in a lipid-rich carcinoma has not been previously reported.

Objectives: To assess the possible responsiveness of blink reflex alterations present in dementia with Lewy bodies (DLB) to treatment with cholinesterase inhibitors., Methods: Twenty-six patients with DLB and 20 patients with Alzheimer disease underwent clinical, neuropsychological (including assessment of cognitive fluctuations, with the Cognitive Assessment of Fluctuations and the One-Day Fluctuation Assessment questionnaires), and the blink reflex evaluation at baseline, 1 week after vitamin E administration (to assess test-retest reliability), and 1 and 2 weeks after donepezil administration at the dose of 10 mg/d. Results were compared with data obtained from 30 healthy controls treated with vitamin E capsules for 2 weeks., Results: Treatment with donepezil did not cause modifications of cognitive or motor performances in both groups of patients. In DLB patients, One-Day Fluctuation Assessment scores were modified by donepezil treatment with a mean reduction of 2.8 +/- 1.8 compared with baseline (P < 0.05). After 2 weeks of treatment with donepezil, R2 latency was significantly decreased in DLB patients. The mean R2 latency reduction was by 3.0 +/- 3.2 milliseconds (P < 0.0001 compared with baseline). R2 mean latency reduction was significantly correlated with R2 mean latency delay at baseline (Spearman rho = 0.8)., Conclusions: Short-term donepezil administration can correct the alterations of the blink response together with the daily occurrence of cognitive fluctuations present in DLB patients.

We used a systematic review to identify strategies that have been evaluated for disseminating cancer control interventions that promote the uptake of a healthy diet in adults. Studies were identified by contacting technical experts and by searching MEDLINE, PreMedline, CANCERLIT, EMBASE/Excerpta Medica, Psycinfo, cinahl, the Cochrane Database of Systematic Reviews, and reference lists. English-language primary studies were selected if they evaluated the dissemination of healthy diet interventions to individuals, health care providers, or institutions. Studies involving only children or adolescents were excluded.We retrieved 101 articles for full-text screening, and identified nine reports of seven distinct studies. Four of the studies were randomized trials, one was a cohort design, and three were descriptive studies. Six of the studies were rated methodologically weak, and one was rated moderate. Because of heterogeneity, low methodological quality, and incomplete data reporting, the studies were not pooled for meta-analysis. No beneficial dissemination strategies were found. One strategy involving the use of peer educators at the work site, which led to a short-term increase in fruit and vegetable intake, looks promising.Overall, the quality of the evidence is not strong, and the evidence that exists is more descriptive than evaluative. No clear conclusions can be drawn from these data. Controlled studies are needed to evaluate dissemination strategies and to compare dissemination and diffusion strategies that communicate different messages and target different audiences.

Background: Disease management programmes (DMP) have been advocated to improve long term outcomes of heart failure (HF) patients., Aims: To summarise the evidence supporting DMP effectiveness in improving HF clinical outcomes., Methods: Eligible studies were located through a systematic literature search. Only randomised controlled trials (RCTs), enrolling HF patients, and allocating them to DMP or usual care (UC), were included. Information on study setting and design, participants' characteristics and interventions tested were collected. A study quality assessment was performed. Main clinical outcomes assessed were: all-cause mortality and (re)hospitalisations, HF-related (re)hospitalisations and mortality. Meta-analysis was performed according to both Yusuf-Peto method and random effects model., Results: Thirty-three RCTs were included. Mortality was significantly reduced by DMP compared to UC: OR = 0.80 (CI 0.69-0.93, p = 0.003). All-cause and HF-related hospitalisation rates were also significantly reduced: OR = 0.76 (CI 0.69-0.94, p < 0.00001) and OR = 0.58 (CI 0.50-0.67, p < 0.00001), respectively. Different DMP approaches appeared to be equally effective (sensitivity analyses)., Conclusion: DMP reduce mortality and hospitalisations in HF patients. Because various types of DMP appear to be similarly effective, the choice of a specific programme depends on local health services characteristics, patient population, and resources available.

Objective: The purpose was to determine what strategies have been evaluated to disseminate cancer control interventions that promote the uptake of adult healthy diet?, Methods: A systematic review was conducted. Studies were identified by searching MEDLINE, PREMEDLINE, Cancer LIT, EMBASE/Excerpta Medica, PsycINFO, CINAHL, the Cochrane Database of Systematic Reviews, and reference lists and by contacting technical experts. English-language primary studies were selected if they evaluated the dissemination of healthy diet interventions in individuals, healthcare providers, or institutions. Studies of children or adolescents only were excluded., Results: One hundred one articles were retrieved for full text screening. Nine reports of seven distinct studies were included; four were randomized trials, one was a cohort design and three were descriptive studies. Six studies were rated as methodologically weak, and one was rated as moderate. Studies were not meta-analyzed because of heterogeneity, low methodological quality, and incomplete data reporting. No beneficial dissemination strategies were found except one that looks promising, the use of peer educators in the worksite, which led to a short-term increase in fruit and vegetable intake., Conclusions and Implications: Overall, the quality of the evidence is not strong and is primarily descriptive rather than evaluative. No clear conclusions can be drawn from these data. Controlled studies are needed to evaluate dissemination strategies, and to compare dissemination and diffusion strategies with different messages and different target audiences.

As a new class of pathogens with unusual properties, prions have been implied in several spongiform encephalopathies mainly affecting farm animals (scrapie, mad-cow disease) and humans (kuru, Creutzfeldt-Jacob disease, fatal familial insomnia) (1). The term prions underlines the feature that the agents would merely consist of a protein (2), perhaps a pathological counterpart of a cellular constituent with poorly defined functions (3-5). In reviewing relevant literature, in order to test the validity of the 'protein-only hypothesis' for coherence and consistency with a molecular paradigm, we have met evident discrepancies, making prion diseases a typical abnormality in a Kuhnian sense. This paper summarizes and analyses the main features of the protein-only model.

Live-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine. Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV. Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants. New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome. Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1. We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region. HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells. We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture. As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented. Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable. These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine.

Computerization in breast imaging is very important for activity management and for the qualitative and quantitative control of the diagnoses. The connection through a personal computer network is necessary for the simultaneous input of more data. The activity in our center is completely managed by a specific software which controls and facilitates the input of all personal, administrative, history, instrumental and pathological data. The encoded case history permits quick and accurate data input and the relative information is easy to understand. Database information can be used to make periodical administrative and diagnostic reports and queries, to elaborate useful data for scientific reports and to manage didactic material. The growing use of computers will permit the exchange of data among breast imaging centers and also create important data banks for breast cancer studies.

The 5'-untranslated leader region of human immunodeficiency virus, type 1 (HIV-1), includes a complex array of putative regulatory elements whose role in the viral expression is not completely understood. Here we demonstrate the presence of an NF-kappaB-responsive element in the trans-activation response (TAR) region of HIV-1 that confers the full induction of HIV-1 long terminal repeat (LTR) in response to NF-kappaB-activating stimuli, such as DNA alkylating agents, phorbol 12-myristate 13-acetate, and tumor necrosis factor-alpha. The TAR NF-kappaB site GGGAGCTCTC spans from positions +31 to +40 and cooperates with the NF-kappaB enhancer upstream of the TATA box in the NF-kappaB-mediated induction of HIV-1 LTR. The conclusion stems from the following observations: (i) deletion of the two NF-kappaB sites upstream of the TATA box reduces, but does not abolish, the HIV-1 LTR activation by NF-kappaB inducers; (ii) deletion or base pair substitutions of the TAR NF-kappaB site significantly reduce the HIV-1 LTR activation by NF-kappaB inducers; (iii) deletions of both the NF-kappaB sites upstream of the TATA box and the TAR NF-kappaB site abolish the activation of HIV-1 LTR in response to NF-kappaB inducers. Moreover, the p50 p65 NF-kappaB complex binds to the TAR NF-kappaB sequence and trans-activates the TAR NF-kappaB-directed expression. The identification of an additional NF-kappaB site in the HIV-1 LTR points to the relevance of NF-kappaB factors in the HIV-1 life cycle.

Transcription factors of the NF-kappa B/Rel family are retained in the cytoplasm as inactive complexes through association with I kappa B inhibitory proteins. Several NF-kappa B activators induce the proteolysis of I kappa B proteins, which results in the nuclear translocation and DNA binding of NF-kappa B complexes. Here, we report a novel mechanism of NF-kappa B regulation mediated by p105 (NF-kappa B1) precursor of p50 directly at the nuclear level. In Epstein-Barr virus-immortalized B cells, p105 was found in the nucleus, where it was complexed with p65. In concomitance with NF-kappa B activation, mitomycin C induced the processing of p105 to p50 in the nucleus, while it did not affect the steady-state protein levels of I kappa B alpha and p105 in the cytoplasm. Differently, phorbol 12-myristate 13-acetate induced a significant proteolysis of both I kappa B alpha and p105 in the cytoplasm, while it did not affect the protein level of p105 in the nucleus. These results suggest that in Epstein-Barr virus-positive B cell lines the nuclear processing of p105 can contribute to NF-kappa B activation in response to specific signaling molecules, such as DNA-damaging agents.