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5. Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

Author

Cea, Michele, Cagnetta, Antonia, Fulciniti, Mariateresa, Tai, Yu-Tzu, Hideshima, Teru, Chauhan, Dharminder, Roccaro, Aldo, Sacco, Antonio, Calimeri, Teresa, Cottini, Francesca, Jakubikova, Jana, Kong, Sun-Young, Patrone, Franco, Nencioni, Alessio, Gobbi, Marco, Richardson, Paul, Munshi, Nikhil, and Anderson, Kenneth C.

Published
2012
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12. SDS-Stabilized CuInSe2/ZnS Multinanocomposites Prepared by Mechanochemical Synthesis for Advanced Biomedical Application

Author

Dutková, Erika, primary, Bujňáková, Zdenka Lukáčová, additional, Sphotyuk, Oleh, additional, Jakubíková, Jana, additional, Cholujová, Danka, additional, Šišková, Viera, additional, Daneu, Nina, additional, Baláž, Matej, additional, Kováč, Jaroslav, additional, Briančin, Jaroslav, additional, and Demchenko, Pavlo, additional

Published
2020
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17. Injuries due to foreign body aspirations in Georgia: A prevention perspective

Author

Gvetadze, Paata, Chkhaidze, Ivane, Baldas, Solidea, Comoretto, Rosanna, Gregori, Dario, Berchialla, Paola, Rodriguez, Hugo, Zaupa, Paula, Spitzer, Peter, Demetriades, Costantinos, Šlapák, Ivo, Sokolova, Ljiljana, Petridou, Eleni, Clemente Manuel Antonio, Jakubíková, Jana, Van As Sebastian, De Koning Ton, and The Susy Safe Working Group

Subjects
Choking, Foreign bodies injuries, Georgia, Pediatric injuries, Adolescent, Asphyxia, Child, Child, Preschool, Foreign Bodies, Hospitalization, Humans, Infant, Inhalation Exposure, Registries, Respiratory System, Wounds and Injuries, medicine.medical_specialty, Poison control, Suicide prevention, Occupational safety and health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Injury prevention, Epidemiology, medicine, Preschool, 030223 otorhinolaryngology, Cause of death, business.industry, Public health, General Medicine, medicine.disease, Otorhinolaryngology, Pediatrics, Perinatology and Child Health, business, Demography
Abstract

Background Suffocation due to foreign bodies (FB) is a leading cause of death in children aged 0–3. No data from the former U.S.S.R. are available in the international scientific literature. Methods Consecutive patients admitted at the Iashvili Central Children Hospital in Tbilisi, Georgia from 1989 to 2011 were analyzed. Injuries in the upper airways due to foreign bodies’ inhalation were collected and compared with the Susy Safe Registry and the pooled estimates of the meta-analysis. Results 2896 cases were collected. Distribution of injuries in children younger than 3 years was significantly higher than in the Susy Safe Registry and in the “High-Income” countries in the meta-analysis. Percentage of injuries due to organic objects (86%) was significantly higher than in published data. Conclusions Since Georgia is not showing any substantial difference, both in epidemiology and treatment of foreign bodies injuries, as compared to the other case series, translation of public health initiatives from other most advanced prevention experiences is possible and it is likely to be effective. Level of evidence Level V, Epidemiological case series.

Published
2016

18. Non food foreign body injuries

Author

Slapak, Ivo, Passali, Francesco Maria, Passali, Giulio Cesare, Gulati, Achal, Gregori, Dario, Foltran, Francesca, Ballali, Simonetta, Berchialla, Paola, Rodriguez, Hugo, Zaupa, Paola, Spitzer, Peter, Demetriades, Costantinos, Sokolova, Ljiljana, Petridou, Eleni, D'Alessandro, Antonella, Pais Clemente, Manuel Antonio Caldeira, Jakubíková, Jana, Van As, Sebastian, De Koning, Ton, Passali, Desiderio, Chinsky, Alberto, Brkic, Fuad, Mladina, Ranko, Kalakouta, Olga, Melis, Andreas, Máchalová, Michaela, Thomasen, Per Caye, Elsheikh, Enas, Ragab, Ahmed, Pitkäranta, Anne, Necker, Philippe Contencin, Derelle, Jocelyne, Duwelz, Magali, Francois, Martine, Pezzettigotta, Stephane, Righini, Christian, Stephane, Pezzettigotta, Bernhard, Roehrich, Jahnke, Volker, Onder, Goktas, Zieriacks, Petra, Kalampoki, Vicky, Simasko, Nikola, Skoulakis, Charalampos, Camaioni, Angelo, Cutrone, Cesare, Gaudini, Elisa, Messi, Gianni, Grasso, Domenico, Orlando, Claudio, Nicola Mansi, Mansi, Preziosi, Sabino, Villari, Giuseppe, Sorrentini, Italo, Trozzi, Marilena, Vigo, Alessandro, Nishida, Yoshifumi, Ussatayeva, Gainel, De Hoyos, Ricardo, Ologe, Foluwasayo Emmanuel, Nasrullah, Muazzam, Melendez, Amarilis, Chmielik, Mieckzyslaw, Belchior, Teresa, Cobzeanu, Mihail Dan, Gheorghe, Dan Cristian, Toader, Miorita, Iorgulescu, Lennaert, Codrut, Caius, Barkociová, Jana, Havelkova, Jana, Zargi, Miha, Pumarola, Felix, Rubio, Lorenzo, Stierna, Pontus, Hsu, Wei chung, Arj-Ong, Sakda, Chomchai, Chulathida, Rinkel, Rico, Hoep, Lennaert, Baskent, Erdinc Aydin, Erikci, Volkan Sarper, Onerci, Metin, Graham, John, Khwaja, Sadie, Raine, Christopher, Otolaryngology / Head & Neck Surgery, and CCA - Quality of life

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Perforation (oil well), Poison control, Suicide prevention, Occupational safety and health, Age Distribution, Injury prevention, medicine, Humans, Registries, Sex Distribution, Child, business.industry, Infant, Newborn, Infant, Human factors and ergonomics, General Medicine, Odds ratio, Consumer protection, Foreign Bodies, Surgery, Europe, Hospitalization, Otorhinolaryngology, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business
Abstract

Rationale and aim The aim of the present study is to acquire a better understanding of Non Food Foreign Bodies (NFFB) injuries in children with particular regard to the quantification of the risk of complications and hospitalization associated with patient characteristics, FB features, FB location and circumstances of the accident, as emerging from the SUSY Safe Web-Registry. Methods The present study uses data provided by the SUSY Safe Project, a DG SANCO co-funded project which was aimed to collect as many scientific data as possible regarding Foreign Bodies (FB) injuries in children aged 0–14 years and to serve as a basis for a knowledge-based consumer protection activity in the Europe market. FBs were characterized by size, shape and consistency. Descriptive statistics (absolute and relative number or median, I and III quartile according to the categorical or continuous variable, respectively) were calculated for each considered non food item characteristics; FB features distribution by children class age and site of obstruction were assessed. Two different outcomes were considered: hospitalization and complication. FBs which most frequently cause complications were identified. The association between children age, adult presence, object characteristics and outcomes was computed using crude odds ratios and the related 95% confidence intervals. Results 16,878 FB injuries in children aged 0–14 yrs have been recorded in the Susy Safe databases. FB type was specified in 10,564 cases; among them 7820 (74%) were due to a non food item. Almost two thirds of injuries occurred in patients 3 years or more old. 53% of patients were males, while 47% were females. When injury happened, the great part of children (86%) was playing. Almost 30% (2339) of injuries happened under adults’ supervision. Complications occurred in 299 cases and the most documented was infections (10% of cases) followed by perforation (5%). Conclusions The inhalation/aspiration of a FB, as well as the ingestion and the insertion in the orifices of a FB may result in significant morbidity. Particularly, long-standing or hazardous foreign bodies can cause extensive damage. Some objects, because of their composition, contour, or location, are particularly hazardous: for instance, objects with sharp edges pose a significant risk of laceration and perforation, while fragments of toys have been found only in 2 cases. Parents are frequently unconscious of hazard related with some objects and they are not adequately able to promptly recognize dangerous objects and risky situations. Moreover, also clinicians seem to pay little attention to adult role in the dynamic of the accident: in fact in case series descriptions, data regarding adult presence are often under-reported. On the contrary, since many injuries to children cannot be prevented without some degree of active behavior on the part of parents, the dissemination of information regarding safe behaviors and the implementation of educational strategies aiming to improve parent's attention toward this issue could be fundamental in preventing injuries and need to be promoted by family pediatricians and health practitioners.

Published
2012

21. Symptoms associated with button batteries injuries in children: An epidemiological review

Author

Buttazzoni, Elisa, Gregori, Dario, Paoli, Bibiana, Soriani, Nicola, Baldas, Solidea, Rodriguez, Hugo, Lorenzoni, Giulia, Marquez, Claudio Rene, Cuestas, Giselle, Sica, Graciela, Berchialla, Paola, Zaupa, Paola, Spitzer, Peter, Demetriades, Costantinos, Ŝlapák, Ivo, Sokolova, Ljiljana, Petridou, Eleni, Antonio, Manuel, Jakubíková, Jana, Sebastian Van, As, Koning, Ton De, Passali, Desiderio, Bouchikhi, Nourredine, Boufersaoui, Abderrahmane, Chinsky, Alberto, Tortosa, Susana, Blasio, Andrea Di, Rodriguez, Veronica, Taire, Damian, Razetti, Juan, Mariotti, Carlos Adolfo, Ariel, Achával Héctor, Zanetta, Adrian, Dario, Fajre, Pabón, Sonia Milena, Quijano, Alejandro, Nieto, Marìa Elena, Bordino, Lucas, Dallakyan, Nikolay, Dallakyan, David, Villca, Nelson, Brkic, Fuad, Umihanic, Sekib, Reis, Marcelo, Manrique, Dayse, Nkodo, Yves, Ludemann, Jeffrey, Chengpeng, Jiang, Puentes, Oscar Uriel Barón, Mladina, Ranko, De La Rosa, Evians Gomez, Kalakouta, Olga, Melis, Andreas, Zeitouni, Florence, Máchalová, Michaela, Slapak, Jan, Pecková, Pavla, Caye-Thomasen, Per, Chacon, Fernando Silva, Parker, John, Elsheikh, Enas, Ragab, Ahmed, Pitkäranta, Anne, Necker, Philippe Contencin, Derelle, Jocelyne, Duwelz, Magali, Francois, Martine, Pezzettigotta, Stephane, Righini, Christian, Chkhaidze, Ivane, Bernhard, Roehrich, Jahnke, Volker, Onder, Goktas, Zieriacks, Petra, Siegfried, Klaue, Koitschev, Assen, Kalampoki, Vicky, Simasko, Nikola, Skoulakis, Charalampos, Gulati, Achal, Nimbalkar, Somashekhar, Sharma, Yojana, Squicciarini, Marco, Damasco, Mirko, Camaioni, Angelo, Cutrone, Cesare, Gaudini, Elisa, Grassom, Domenico, Messi, Gianni, Mansi, Nicola, Orlando, Claudio, Preziosi, Sabino, Sorrentini, Italo, Villari, Giuseppe, Trozzi, Marilena, Vigo, Alessandro, Passali, Giulio Cesare, Passali, Francesco Maria, Piantanida, Renato, Giordano, Carlo, Mercuri, Leonardo, Cecconi, Alessandro, Giovari, Matteo, Calderini, Edoardo, Nishida, Yoshifumi, Saito, Tadashi, Ussatayeva, Gainel, De Hoyos Parra, Ricardo Antonio, Treviño Gonzalez, Jose Luis, Ramayo, Seraides, Ologe, Foluwasayo Emmanuel, Afolabi, Olushola, Nasrullah, Muazzam, Melendez, Amarilis, Milanes, Rafael, Chmielik, Mieckzyslaw, Belchior, Teresa, Cobzeanu, Mihail Dan, Gheorghe, Dan Cristian, Iorgulescu, Adelaida, Toader, Miorita, Codrut, Caius, Stankovic, Katarina, Barkociová, Jana, Havelkova, Beata, Jakubikova, Janka, Koman, Andrej, Zargi, Miha, Pumarola, Felix, Rubio, Lorenzo, Peco, Karina Pernías, Stierna, Pontus, Hsu, Wei-Chung, Arj-Ong, Sakda, Chomchai, Chulathida, Chotigavanich, Chanticha, Hoep, Lennaert, Rinkel, Rico, Berraies, Anissa, Baskent, Erdinc Aydin, Erikci, Volkan Sarper, Onerci, Metin, Graham, John, Khwaja, Sadie, Raine, Christopher, Haloob, Nora, Haedo, Ines Doassans Gómez, Mehta, Deepak, Casselbrant, Margaretha, and Toan, Pham Ngoc

Subjects
Male, Pediatrics, Databases, Factual, Poison control, Eating, Registries, Child, Nose, Button batteries, Children injuries, Choking, Foreign bodies, Ingestion, Adolescent, Child, Preschool, Cough, Crying, Deglutition Disorders, Epidemiologic Studies, Esophagus, Female, Fever, Foreign Bodies, Humans, Infant, Infant, Newborn, Inhalation, Mouth, Nasal Cavity, Sialorrhea, Stomach, Symptom Assessment, Electric Power Supplies, Otorhinolaryngology2734 Pathology and Forensic Medicine, General Medicine, Perinatology and Child Health, Dysphagia, medicine.anatomical_structure, Settore MED/31 - OTORINOLARINGOIATRIA, medicine.symptom, medicine.medical_specialty, Pediatrics, Perinatology and Child Health, Irritability, Drooling, Databases, Injury prevention, medicine, Preschool, Factual, business.industry, medicine.disease, Newborn, Otorhinolaryngology, Foreign body, business
Abstract

Objectives To provide an epidemiological framework of symptoms related to Foreign Body (FB) injuries due to Button Battery (BB). Methods Data on BB ingestion/inhalation have been obtained from the ButtonBatteryDB. The ButtonBatteryDB is a database collecting information on BB injuries in children (0–18 years of age). Data on 348 BB injures have been derived from the Registry of Foreign Body Injuries “Susy Safe” (269 cases) and from published scientific literature reporting case reports of FB injuries (79 cases). Results Most of injured children were male and BBs were found more often in the mouth/esophagus/stomach (ICD935) and in the nose (ICD932). Analyzing symptoms related to BB located in the esophagus/mouth/stomach, we found that children had higher probability of experiencing dysphagia (30.19%, 95% C.I. 17.83–42.55), fever and cough (26.42%, 95% C.I. 14.55–38.28), compared to the other symptoms. Referring to the probability that symptoms occurred simultaneously, fever and cough are more likely (3.72%, 95% C.I. 1.0–6-43) to jointly showing up in children with BB in mouth/esophagus/stomach (ICD935), followed by fever and dysphagia (2.66%, 95% C.I. 0.36–4.96) and by fever and irritability/crying, fever and drooling, dysphagia and irritability/crying (2.13% C.I. 0.00–4.19, 95% C.I.) Conclusions These findings provide new insight in clinical presentation of BB injuries: the identification of unique patterns of symptoms related to BB injuries is useful to perform an early diagnosis (and to guarantee a prompt medical reaction), also when the injury is un-witnessed.

Published
2015

24. Food foreign body injuries

Author

Sebastian van As, Arjan B., Yusof, Abdullah M., Millar, Alastair J.W., Gregori, Dario, Foltran, Francesca, Ballali, Simonetta, Berchialla, Paola, Rodriguez, Hugo, Zaupa, Paola, Spitzer, Peter, Demetriades, Costantinos, Slapák, Ivo, Sokolova, Ljiljana, Petridou, Eleni, D'Alessandro, Antonella, Clemente, Manuel Antonio Caldeira Pais, Jakubíková, Jana, As, Sebastian Van, Koning, Ton De, Passali, Desiderio, Chinsky, Alberto, Brkic, Fuad, Mladina, Ranko, Kalakouta, Olga, Melis, Andreas, Máchalová, Michaela, Caye-Thomasen, Per, Elsheikh, Enas, Ragab, Ahmed, Pitkäranta, Anne, Necker, Philippe Contencin, Derelle, Jocelyne, Duwelz, Magali, Francois, Martine, Pezzettigotta, Stephane, Righini, Christian, Stephane, Pezzettigotta, Buzarov, Jane, Bernhard, Roehrich, Jahnke, Volker, Onder, Goktas, Zieriacks, Petra, Kalampoki, Vicky, Simasko, Nikola, Skoulakis, Charalampos, Camaioni, Angelo, Cutrone, Cesare, Gaudini, Elisa, Grasso, Domenico, Mansi, Nicola, Messi, Gianni, Orlando, Claudio, Preziosi, Sabino, Sorrentini, Italo, Trozzi, Marilena, Vigo, Alessandro, Villari, Giuseppe, Passali, Giulio Cesare, Passali, Francesco Maria, Nishida, Yoshifumi, Ussatayeva, Gainel, Hoyos, Ricardo De, Ologe, Foluwasayo Emmanuel, Nasrullah, Muazzam, Melendez, Amarilis, Chmielik, Mieckzyslaw, Belchior, Teresa, Cobzeanu, Mihail Dan, Gheorghe, Dan Cristian, Iorgulescu, Adelaida, Caius-Codrut, Toader, Miorita, Barkociová, Jana, Havelkova, Beata, Zargi, Miha, Sebastian van As, A. B., Pumarola, Felix, Rubio, Lorenzo, Stierna, Pontus, Hsu, Wei Chung, Arj-Ong, Sakda, Chomchai, Chulathida, Hoep, Lennaert, Rinkel, Rico, Baskent, Erdinc Aydin, Erikci, Volkan Sarper, Onerci, Metin, Graham, John, Khwaja, Sadie, Raine, Christopher, and Otolaryngology / Head & Neck Surgery

Subjects
Larynx, Male, medicine.medical_specialty, Pediatrics, Adolescent, Poison control, Atelectasis, Age Distribution, Injury prevention, medicine, Humans, Prospective Studies, Registries, Esophagus, Sex Distribution, Child, Nose, business.industry, Pharynx, Infant, Newborn, Infant, General Medicine, medicine.disease, Foreign Bodies, Surgery, Europe, Hospitalization, medicine.anatomical_structure, Otorhinolaryngology, Food, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Foreign body, business
Abstract

Rationale and aim: The purpose of this study is to acquire a better understanding of Food Foreign Bodies (FFB) injuries in children characterizing the risk of complications and prolonged hospitalization due to food items according to patients' characteristics, circumstances of the accident, Foreign Body (FB) features and FB location, as emerging from the SUSY Safe Web-Registry. Methods: The present study uses data provided by the SUSY Safe Project, a DG SANCO co-funded project started in February 2005, which was aimed at establishing an international registry of cases of Foreign Bodies (FB) injuries in children aged 0-14 years. The analysis was carried out on injuries due to a food item.FB location was reported according to ICD9-CM code: ears (ICD931), nose (ICD932), pharynx and larynx (ICD933) trachea, bronchi and lungs (ICD934), mouth, esophagus and stomach (ICD935).Age and gender injury distributions were assessed. Data regarding adult supervision and activity before injury were also evaluated. FBs which most frequently cause complications were identified. The association between children age, adult presence, object characteristics and hospitalization/complications was computed using unweighted odds ratios and the related 95% confidence intervals. Results: 16,878 FB injuries occurred in children aged 0-14 years have been recorded in the SUSY Safe databases. FB type was specified in 10,564 cases; among them 2744 (26%) were due to a food item. FB site was recorded in 1344 cases: FB was located in the ears in 99 patients, while 1140 occurred in the upper and lower respiratory tract; finally, 105 food items were removed from mouth, esophagus and stomach. Complications occurred in 176 cases and the most documented was pulmonary or bronchial infections (23%) followed emphysema or atelectasis and by and asthma (7%). Bones were the commonest retrieved FFB encountered in this study, while nuts seem to be the FFB most frequently associated to complications. Conclusions: On the basis of this study we make the strong recommendation that parents should be adequately educated and provide age-appropriate food to their children and be present in order to supervise them during eating especially during a critical period ranging from 2 to 3 years of age.

Published
2012

25. The influence of the modification of food intake habits on the development of the cancer

Author

Pastorek, Michal, Jakubíková, Jana, Siekel, Peter, and Sedlák, Ján

Subjects
Slovakia, Opinion, isothiocyanates, cancer prevention, food, glucosinolates
Abstract

Glucosinolates and their metabolites isothiocyanates if presented in food are capable to inhibit occurence of cancer in experimental animals. Their consumption in food lowers the risk of the incidence of lung, prostate, breast and colon cancer in man. The effect of isothiocyanates depends on the quantity (concentration) used and also on the genetic background of cells used in the experiment. The chemo-preventive effect of the isothiocyanates is based on the modulation of enzymes which are necessary for activation or detoxification od carcinogens and also on the inhibition pro-inflammatory and pro-angiogenic signal pathways. Isothiocyanates boost cytotoxic effect of chemotherapeutics, increase the sensitivity of cells to the TRAIL, modify epigenetic regulation of gene expression, modulate epithelium - mesenchymal transition and are effective against TIC cells., SK; sk; efsa.focalpoint@land.gov.sk

Published
2009
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35. The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo

Author

Rozic, Gabriela, Paukov, Lena, Jakubikova, Jana, Ben-Shushan, Dikla, Duek, Adrian, Leiba, Adi, Avigdor, Abraham, Nagler, Arnon, and Leiba, Merav

Subjects
multiple myeloma, cell cycle, apoptosis, tubulin, AKT
Abstract

Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM.

Published
2016
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36. A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche: biologic and clinical applications

Author

Jakubikova, Jana, Cholujova, Danka, Hideshima, Teru, Gronesova, Paulina, Soltysova, Andrea, Harada, Takeshi, Joo, Jungnam, Kong, Sun-Young, Szalat, Raphael E., Richardson, Paul G., Munshi, Nikhil C., Dorfman, David M., and Anderson, Kenneth C.

Subjects
multiple myeloma, tumor microenvironment, mesenchymal stem cells, 3D model, drug resistance
Abstract

Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM.

Published
2016
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41. Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells

Author

Jakubíková, Jana, Sedlák, Ján, Mithen, Richard, and Bao, Yongping

Subjects
*PROTEIN kinases, *ENZYMES, *DRUG resistance, *APOPTOSIS
Abstract

Abstract: Isothiocyanate sulforaphane is an extensively studied cancer chemopreventive agent in human diet. In this study, the effects of sulforaphane (SFN) and its sulfide analog, erucin (ERN), have been examined on the induction of the phase II enzymes, quinine oxidoreductase (NQO1) and UDP-glucuronosyl transferase (UGT1A1), multidrug transporter (MRP2), cell cycle arrest and cell death in human colon adenocarcinoma Caco-2 cells. Additionally, the roles of PI3K/Akt and MEK/ERK signaling pathways have been assessed in these sulforaphane- and erucin-induced events. Although erucin and sulforaphane have similar IC50 values (21 and 23μM after 72h treatment), erucin was more effective in the induction of G2/M accumulation, depletion of mitochondrial potential, induction of cell death and mRNA induction of phase II enzymes and MRP2. Erucin (20μM) induced the mRNAs of NQO1, UGT1A1 and MRP2 by 11.1-, 11.6- and 6.7-fold, whereas sulforaphane (20μM) induced 3.3-, 5.3- and 2.2-fold, respectively. Both erucin and sulforaphane induced activation (phosphorylation) of ERK1/2 and Akt kinases but had no effect on JNK and p38 activation. Erucin-induced phase II enzyme transcriptions were decreased by PI3K and MEK1 inhibitors (LY294002 and PD98059), but the decreases in sulforaphane-induced transcription were less marked. Erucin induced a large increase in G2/M cell number than sulforaphane. The ability of kinase inhibitors to overcome G2/M block was low with the exception of PD98059 in sulforaphane-treated cells. Both, sulforaphane and erucin at high concentrations induced accumulation of sub-G1 cells, cell death and dissipation of mitochondrial membrane potential. Taken together, these results demonstrate that PI3K/Akt and MEK/ERK signals are important intracellular mediators in erucin- and sulforaphane-mediated phase II enzyme transcription and cell cycle arrest in Caco-2 cells. [Copyright &y& Elsevier]

Published
2005
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43. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells

Author

Suzuki, Rikio, Kikuchi, Shohei, Harada, Takeshi, Mimura, Naoya, Minami, Jiro, Ohguchi, Hiroto, Yoshida, Yasuhiro, Sagawa, Morihiko, Gorgun, Gullu, Cirstea, Diana, Cottini, Francesca, Jakubikova, Jana, Tai, Yu-Tzu, Chauhan, Dharminder, Richardson, Paul G., Munshi, Nikhil, Ando, Kiyoshi, Utsugi, Teruhiro, Hideshima, Teru, and Anderson, Kenneth C.

Abstract

Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM.

Published
2015
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44. Blockade of Nuclear Export Protein CRM1 (chromosomal region maintenance 1, XPO1) by a Novel, Potent and Selective CRM1 Inhibitor KPT-185 Induces Significant Antitumor Activity Against Human Multiple Myeloma

Author

Kong, Sun-Young, Landesman, Yosef, Jakubikova, Jana, Sellitto, Michael A., Cagnetta, Antonia, Cea, Michele, Chen, Michelle C., Cottini, Francesca, McMillin, Douglas W., Acharya, Chirag, Senapedis, William, Shacham, Sharon, Kauffman, Michael, McCauley, Dilara, Saint-Martin, Jean-Richard, Munshi, Nikhil C., Richardson, Paul G., Anderson, Kenneth C., and Tai, Yu-Tzu

Published
2011
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46. Proteasome Inhibitors Sensitize Myeloma Cells to T Cell-Mediated Killing

Author

van de Donk, Niels W.C.J., Lokhorst, Henk M., Emmelot, Maarten, Aarts-Riemens, Tineke, McMillin, Douglas W., Gorgun, Gullu, Klippel, Steffen, Dhimolea, Eugen, Jakubikova, Jana, Hayes, Catriona A., Lawasut, Panisinee, Delmore, Jake E, Munshi, Nikhil C., Richardson, Paul G., Anderson, Kenneth C., Mitsiades, Constantine S., and Mutis, Tuna

Published
2011
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49. Molecular and cellular influences of butylated hydroxyanisole on Chinese hamster V79 cells treated with <TOGGLE>N</TOGGLE>-methyl-<TOGGLE>N</TOGGLE>'-nitro-<TOGGLE>N</TOGGLE>-nitrosoguanidine: Antimutagenicity of butylated hydroxyanisole

Author

Slameňová, Darina, Horváthová, Eva, Robichová, Soňa, Hrušovská, L'ubica, Gábelová, Alena, Kleibl, Karol, Jakubíková, Jana, and Sedlák, Ján

Abstract

The antioxidant butylated hydroxyanisole (BHA) is a rodent carcinogen that also reduces the mutagenicity and carcinogenicity of other agents. In this study, we have evaluated possible mechanisms for the antimutagenicity of BHA by investigating its effects on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated Chinese hamster V79 cells. Mutant frequency was determined using the hprt/V79 assay, while plating efficiency was used to measure cytotoxicity, and apoptosis was measured by flow immunofluorocytometry. In addition, DNA strand breaks and the kinetics of strand-break rejoining were investigated by the alkaline elution of DNA and by single-cell gel electrophoresis (SCGE). Although the higher concentration of BHA (0.5 mM) increased the cytotoxicity of MNNG and the lower concentration of BHA (0.25 mM) did not change it, both concentrations were antimutagenic in MNNG-treated cells, with the greater effect occurring at the lower BHA concentration. Neither BHA nor MNNG nor BHA + MNNG increased the level of apoptotic nuclei, and BHA did not change the level of MNNG-induced DNA strand breaks, though it did inhibit their rejoining. Determination of O6-methylguanine-DNA-methyltransferase (MGMT) activity confirmed that V79 cells do not synthesize active MGMT protein; MGMT activity was also undetectable after MNNG and BHA + MNNG treatment. The ability of BHA to reduce the level of MNNG-induced mutations did not correlate with cytotoxicity, induction of apoptosis, the level of DNA strand break induction, or MGMT activity. A modified SCGE assay showed that BHA significantly reduced the level of formamidopyrimidine-DNA-glycosylase + endonucleaseIII-sensitive sites, which at least partially are caused by oxidative DNA lesions. The results suggest that the protective effect of BHA on MNNG-induced mutagenicity is best explained by the antioxidative activity of BHA, which may scavenge free radicals that participate in MNNG-induced mutagenicity. Environ. Mol. Mutagen. 41:28–36, 2003. © 2003 Wiley-Liss, Inc.

Published
2003
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