Fabricación y caracterización de aleaciones porosas de Ti y Ti6Al4V producidas mediante sinterización con espaciador

[ES] El titanio es un material biocompatible que, además de presentar buenas propiedades a la corrosión, posee una elevada resistencia mecánica teniendo en cuenta su baja densidad. En el campo de la pulvimetalurgia, entre otras aplicaciones, este material se usa con objeto de obtener materiales porosos para aplicaciones biomédicas. Recientemente se ha investigado la aplicación de los materiales porosos en la fabricación de implantes de cadera. La razón principal está basada en la reducción de la rigidez de los implantes, lo cual minimiza los efectos del ¿apantallamiento de tensiones¿, al aproximarse su módulo elástico al del hueso. El propósito del presente trabajo, es producir materiales porosos mediante la técnica de sinterización con espaciador, usando el bicarbonato de amonio como propulsor de la formación de poros. Para la obtención de los mismos, se ha utilizado polvo de titanio de diferentes tamaños de partícula, usando diversas presiones de compactación. Antes de realizar la sinterización, se han evaluado las propiedades mecánicas de las muestras en verde, de modo que se permita su manipulación. Tras realizar la sinterización, se ha evaluado la densidad y porosidad. Igualmente, se ha valorado el efecto de estas variables en las propiedades mecánicas y el módulo elástico, obtenidos mediante el ensayo de flexión a tres puntos. La caracterización microestructural se ha realizado mediante microscopía óptica y electrónica.[EN] Titanium is well-known to be a biocompatible material with good corrosion properties and good strength, taking into account their low specific weight. In powder metallurgy field, titanium has been used in order to obtain porosity materials for biomedical applications. Recently, porous materials have been investigated for their use like hips implants. The principal reason is based on a reduction of stiffness implants, minimizing effects of stress shielding. The purpose of the present work is produced porous materials by space holder technique using ammonium bicarbonate like spacer. Scaffolds of titanium have been fabricated by powders of titanium with different grades of particle size and compacting pressure. Before sintering, stability of green parts has been studied by mechanical test. After sintering, porosity has been evaluated besides mechanical properties and elastic modulus by three points bending test. The microstructural characterisation is performed by optical and electron microscopy.Tojal Domenech, C.; Amigó Borrás, V.; J.A. Calero (2013). Fabricación y caracterización de aleaciones porosas de Ti y Ti6Al4V producidas mediante sinterización con espaciador. Revista de Metalurgia. 49(1):20-30. doi:10.3989/revmetalm.1206S2030491Montealegre-Melendez, I., Neubauer, E., & Danninger, H. (2009). Effect of starting powder grade on sintering and properties of PM titanium metal matrix composites. Powder Metallurgy, 52(4), 322-328. doi:10.1179/174329009x457117Eriksson, M., Andersson, M., Adolfsson, E., & Carlström, E. (2006). Titanium–hydroxyapatite composite biomaterial for dental implants. Powder Metallurgy, 49(1), 70-77. doi:10.1179/174329006x94591Schiefer, H., Bram, M., Buchkremer, H. P., & Stöver, D. (2009). Mechanical examinations on dental implants with porous titanium coating. Journal of Materials Science: Materials in Medicine, 20(8), 1763-1770. doi:10.1007/s10856-009-3733-1Amigó, V., Salvador, M. D., Romero, F., Solves, C., & Moreno, J. F. (2003). Microstructural evolution of Ti–6Al–4V during the sintering of microspheres of Ti for orthopedic implants. Journal of Materials Processing Technology, 141(1), 117-122. doi:10.1016/s0924-0136(03)00243-7[6] H.D. Kunze, Metal Powder Report 50 (1995) 36.Esen, Z., & Bor, Ş. (2007). Processing of titanium foams using magnesium spacer particles. Scripta Materialia, 56(5), 341-344. doi:10.1016/j.scriptamat.2006.11.010Robertson, I. M., & Schaffer, G. B. (2010). Swelling during sintering of titanium alloys based on titanium hydride powder. Powder Metallurgy, 53(1), 27-33. doi:10.1179/003258909x12502872942534Li, C. F., Zhu, Z. G., & Liu, T. (2005). Microhardness of pore walls in porous titanium prepared with novel powder metallurgy. Powder Metallurgy, 48(3), 237-240. doi:10.1179/174329005x64162Euh, K., Lee, J., Lee, S., Koo, Y., & Kim, N. J. (2001). Microstructural modification and hardness improvement in boride/Ti–6Al–4V surface-alloyed materials fabricated by high-energy electron beam irradiation. Scripta Materialia, 45(1), 1-6. doi:10.1016/s1359-6462(01)00981-2De Oliveira, M. V., Moreira, A. C., Appoloni, C. R., Lopes, R. T., Pereira, L. C., & Cairo, C. A. A. (2006). Porosity Study of Sintered Titanium Foams. Materials Science Forum, 530-531, 22-28. doi:10.4028/www.scientific.net/msf.530-531.22Azevedo, C. R. F., Rodrigues, D., & Beneduce Neto, F. (2003). Ti–Al–V powder metallurgy (PM) via the hydrogenation–dehydrogenation (HDH) process. Journal of Alloys and Compounds, 353(1-2), 217-227. doi:10.1016/s0925-8388(02)01297-5Esteban, P. G., Bolzoni, L., Ruiz-Navas, E. M., & Gordo, E. (2011). Introducción al procesado pulvimetalúrgico del titanio. Revista de Metalurgia, 47(2), 169-187. doi:10.3989/revmetalmadrid.0943Amigó, V., Reig, L., Busquets, D. J., Ortiz, J. L., & Calero, J. A. (2011). Analysis of bending strength of porous titanium processed by space holder method. Powder Metallurgy, 54(1), 67-70. doi:10.1179/174329009x409697Reig, L., Amigó, V., Busquets, D., & Calero, J. A. (2011). Stiffness variation of porous titanium developed using space holder method. Powder Metallurgy, 54(3), 389-392. doi:10.1179/003258910x12707304455068Bram, M., Schiefer, H., Bogdanski, D., Köller, M., Buchkremer, H., & Stöver, D. (2006). Implant surgery: How bone bonds to PM titanium. Metal Powder Report, 61(2), 26-31. doi:10.1016/s0026-0657(06)70603-8[20] R.M. German, Powder Metallurgy and Particulate Materials Processing, Metal Powder Industries Federation, New Jersey, USA, 2005, pp.121-260.[22] L.J. Gibson y M.F. Ashby, Cellular Solids: Structure and Properties, 2nd ed., Cambridge University Press, Cambridge, UK, 1997, pp. 175-231.[23] R.M. German, Powder Metallurgy Science, 2nd ed., Metal Powder Industries Federation, New Jersey, USA, 1994, pp.241-299.[24] R.M. German, G.L. Messing y R. G. Cornwall, Sintering Technology, Marcel Dekker inc., New York, USA, 1996, pp. 349-430.[2] E. Benavente-Martínez, F. Devesa y V. Amigó, Rev. Metal. Madrid 46 (Nº extra) (2010) 19-25.[7] G. Ryan, A. Pandit y D.P. Apatsidis, Biomaterials 27 (2006) 2.651-2.670.[9] C. Aparicio, F. J. Gil, A. Padrós, C. Peraire y J. A. Planell, Rev. Metal. Madrid 34 (Nº. extra) (1998) 184-189.[19] X. Zhao, H. Sun, L. Lan, J. Huang, H. Zhang y Y. Wang, Mater. Lett. 63 (2009) 2.402–2.404.[21] C. Tojal, J. Devaud, V. Amigó y J.A. Calero, Rev. Metal. Madrid 46 (Nº extra) (2010) 26-32.[25] C. Leyens y M. Peters, Titanium and Titanium Alloys. Fundamentals and Applications, ed.Wiley VchGmbh&Co., Weinheim, Alemania, 2003, pp. 423-424

Multiple sclerosis and motherhood choice: an observational study in Portuguese women patients.

INTRODUCTION. Multiple sclerosis (MS) is a disabling disease occurring mainly in women of childbearing age. MS may interfere with family planning and motherhood decision. AIM. To study the influence of MS diagnosis and course of the disease on motherhood decision. PATIENTS AND METHODS. The cohort of 35 to 45-year-old female patients diagnosed with MS for at least ten years was selected from six Portuguese MS centers. A structured questionnaire was applied to all patients in consecutive consultation days. Clinical records were reviewed to characterize and collect information about the disease and pregnancies. RESULTS. One hundred women were included; mean age at MS diagnosis was 26.3 ± 5.0 years; 90% of the participants presented with a relapsing-remitting MS; 57% had no pregnancies after the diagnosis. MS type and number of relapses were not significantly different between women with or without pregnancies after the diagnosis (p = 0.39 and p = 0.50, respectively). Seventy-seven percent of the patients did not have the intended number of pregnancies. Main reasons given were fear of future disability and the possibility of having relapses. Forty-three women considered that pregnancy might worsen MS. CONCLUSION. In our population, motherhood choice was unrelated to the MS type and the number of relapses. However, a relevant number of women had fewer pregnancies than those intended before MS diagnosis and believed that pregnancy could worsen the disease. An effort to better inform the patients should be made to minimize the impact of MS diagnosis on motherhood decision

Esclerosis múltiple y decisión de la maternidad: estudio observacional en pacientes portuguesas

Introducción. La esclerosis múltiple (EM) es una enfermedad incapacitante que afecta mayoritariamente a mujeres en edad fértil. La EM puede alterar el deseo de crear una familia y concebir hijos. Objetivo. Estudiar la influencia del diagnóstico de la EM y de su evolución sobre la decisión de ser madre. Pacientes y métodos. Se seleccionó una cohorte integrada por pacientes de 35-45 años diagnosticadas de EM desde hacía por lo menos 10 años que eran atendidas en seis centros portugueses. Las participantes respondieron a un cuestionario estructurado en días de consulta consecutivos. Se revisaron las historias clínicas para caracterizar y recabar información sobre la enfermedad y los embarazos. Resultados. Participaron 100 mujeres; la media de edad en el momento del diagnóstico de la EM era de 26,3 ± 5,0 años; el 90% de las participantes presentaba la forma remitente recurrente; el 57% de las pacientes no se habían quedado embarazadas después del diagnóstico. El tipo de EM y el número de recidivas no difirieron de manera significativa entre las mujeres que habían concebido después del diagnóstico y las que no (p = 0,39 y p = 0,50, respectivamente). El 77% no había tenido el número de hijos deseado. Los principales motivos aducidos fueron el temor a la incapacidad futura y la posibilidad de sufrir recidivas. Cuarenta y tres mujeres creían que el embarazo podía agravar la EM. Conclusión. En la población del estudio, la decisión de ser o no ser madre no guardó relación con el tipo de EM ni con el número de recidivas. No obstante, un número relevante de mujeres tuvieron menos embarazos de los que habían desea- do antes de ser diagnosticadas y pensaban que la gestación podía empeorar la enfermedad. Sería conveniente mejorar la información que reciben estas pacientes a fin de minimizar el impacto del diagnóstico de la EM en la decisión de ser madre

Mechanical characterization of porous Ti base alloys produced by sintering space-holder method

[ES] La búsqueda de materiales adecuados para su uso como implante implica una mayor investigación sobre los biomateriales, como lo son el titanio y sus aleaciones. Respecto a sus propiedades mecánicas, se debe garantizar una resistencia mecánica suficiente como para soportar cargas en uso, al igual que su rigidez ha de ser parecida a la del hueso humano. En el presente trabajo se miden diferentes propiedades mecánicas de materiales porosos de titanio y de la aleación Ti6Al4V, producidos por vía pulvimetalúrgica mediante sinterización con espaciador. Los resultados muestran la relación entre la porosidad y las propiedades mecánicas, indicando los casos en los que se presenta un compromiso entre la rigidez y la resistencia mecánica.[EN] The search of suitable materials for use as an implant involves more research of biomaterials, like titanium and its alloys. Regarding their mechanical properties, it must be guaranteed mechanical strength to support loads in use, as well as its stiffness must be similar to the bone. In this paper it have been measured several mechanical properties of porous titanium and Ti6Al4V alloy, produced by sintering powder metallurgy with space-holder method. The results show the relationship between porosity and mechanical properties and it is indicated in which cases it is presented a compromise between the stiffness and mechanical strength.Los autores agradecen al área de Ciencia de Materiales e Ingeniería Metalúrgica de la Universidad de Sevilla la ayuda prestada en el cálculo de la rigidez por ultrasonidos. Igualmente, los autores desean agradecer la financiación obtenida por el Ministerio de Ciencia e Innovación (proyecto PET2008_0158_02) y a la beca Grisolia /2009/040.Tojal Domenech, C.; Devaud, J.; Amigó, V.; Calero, JA. (2010). Caracterización mecánica de aleaciones porosas, base Ti, producidas mediante la técnica de sinterización con espaciador. Revista de Metalurgia. 46:27-32. https://doi.org/10.3989/revmetalmadrid.02.2XIIPMSS27324

Synthesis, crystal structure, spectroscopic characterization, DFT calculations and cytotoxicity assays of a new cu(II) complex with an acylhydrazone Ligand derived from thiophene

A new Cu(II) complex is synthetized by the reaction of copper nitrate and a N-acylhydrazone ligand obtained from the condensation of o-vanillin and 2-thiophecarbohydrazide (H2L). The solid-state structure of [Cu(HL)(H2O)](NO3)·H2O, or CuHL for simplicity, was determined by X-ray diffraction. In the cationic complex, the copper center is in a nearly squared planar environment with the nitrate interacting as a counterion. CuHL was characterized by spectroscopic techniques, including solid-state FTIR, Raman, electron paramagnetic resonance (EPR) and diffuse reflectance and solution UV-Vis electronic spectroscopy. Calculations based on the density functional theory (DFT) assisted the interpretation and assignment of the spectroscopic data. The complex does not show relevant antioxidant activity evaluated by the radical cation of 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) method, being even less active than the free ligand as a radical quencher. Cytotoxicity assays of CuHL against three human tumor cell lines, namely MG-63, A549 and HT-29, revealed an important enhancement of the effectiveness as compared with both the ligand and the free metal ion. Moreover, its cytotoxic effect was remarkably stronger than that of the reference metallodrug cisplatin in all cancer cell lines tested, a promissory result in the search for new metallodrugs of essential transition metals.Fil: Rodríguez, María R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Balsa, Lucia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Piro, Oscar Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Etcheverría, Gustavo A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: García Tojal, Javier. Universidad de Burgos; EspañaFil: Pis Diez, Reinaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Leon, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Parajón Costa, Beatriz Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Gonzalez Baro, Ana Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; Argentin

Cu(ii) and Zn(ii) complexes with a poly-functional ligand derived from o-vanillin and thiophene. Crystal structure, physicochemical properties, theoretical studies and cytotoxicity assays against human breast cancer cells

The interaction of a poly-functional ligand derived from o-vanillin and 2-thiophenemethylamine (oVATPNH2) with transition metal ions Cu(II) and Zn(II) leads to the formation of stable coordination compounds, namely [Cu(oVATPNH2)2] and [Zn(oVATPNH2)2]. Their crystal structures have been determined by X-ray diffraction methods. Two molecules of the deprotonated ligand acting in a bidentate fashion build a nearly square planar environment around Cu(II) and a distorted tetrahedral coordination arrangement for Zn(II). The complexes were characterized by spectroscopic techniques, including solid state FTIR, Raman, EPR and diffuse reflectance and solution UV-vis and EPR. Their thermal behavior has been analyzed by means of TGA and DTA. DFT theoretical studies, using computational methods based on DFT, were employed to assist the interpretation and assignment of spectroscopic data. Cytotoxicity assays against two human breast cancer cell lines, namely MCF-7 and MDA-MB-231, revealed an enhancement of the effectiveness of the complexes as compared with both the ligand and the free metal ions. The results for the copper compound are promising, as its cytotoxic effect was stronger than the reference metallodrug cisplatin in both cancer cell lines tested.CONICET-CCT-La Plata (PIP 0651 and 0034), ANPCyT (PICT 2016-1574) and UNLP (11/X-473) (Argentina) and also by Consejerı´a de Educacio´n CyL and FFEDER BU076U16, BU022G18 and Ministerio de Economı´a y Competitividad CTQ2016-75023-C2-1-P and CTQ2015-70371- REDT MetDrugs Network (Spai

Synthesis, crystal structure and cytotoxicity assays of a copper(II) nitrate complex with a tridentate ONO acylhydrazone ligand. Spectroscopic and theoretical studies of the complex and its ligand

The new copper complex, [Cu(HL)(OH2)2](NO3), including the tridentate N-acyhydrazone derived from 4-hydroxy-benzohydrazide and 2-hydroxy-3-methoxybenzaldehyde, (H2L), has been synthesized and characterized in the solid state and in solution by spectroscopic (FTIR, Ra, UV–vis, EPR) methods. The results were compared with those obtained for the hydrazone ligand and complemented with computational methods based on DFT. The crystal structure of the complex has been determined by X-ray diffraction. It crystallizes in the triclinic space group with Z = 2. The Cu(II) ion is in a distorted square pyramidal environment, coordinated to a planar HL- anion acting as a tridentate ligand. The 5-fold coordination is completed with two water molecules. It is arranged in the lattice as H-bonded ribbon-like polymers that extends along the [1 2 1] crystal direction. The cytotoxicity of the complex together with that of the H2L ligand and the copper ion were evaluated in vitro against five different human cancer cell lines namely A549 (lung), MG-63 (bone), MCF-7 and MDA-MB-231 (breast) and Jurkat (leukemia). The copper complex inhibits the cell viability in a dose dependent manner with a greater potency than the H2L ligand and the free copper ion displaying even higher antitumor activity than the well-known anticancer metallodrug cisplatin.CONICET (PIP 11220130100651CO and PIP 0034), UNLP (111/X673) and ANPCyT (PICT 2014-2223) of Argentina. Consejería de Educación CyL and FFEDER BU076U16, BU022G18 and Ministerio de Economía y Competitividad CTQ2016-75023-C2-1-P and CTQ2015-70371-REDTMetDrugs Network (Spain

Germline variants in early and late-onset Brazilian prostate cancer patients

[Background]: The median age for Prostate Cancer (PCa) diagnosis is 66 years, but 10% are diagnosed before 55 years. Studies on early-onset PCa remain both limited and controversial. This investigation sought to identify and characterize germline variants within Brazilian PCa patients classified as either early or later onset disease.[Methods]: Peripheral blood DNA from 71 PCa patients: 18 younger (≤ 55 years) and 53 older (≥ 60 years) was used for Targeted DNA sequencing of 20 genes linked to DNA damage response, transcriptional regulation, cell cycle, and epigenetic control. Subsequent genetic variant identification was performed and variant functional impacts were analyzed with in silico prediction.[Results]: A higher frequency of variants in the BRCA2 and KMT2C genes across both age groups. KMT2C has been linked to the epigenetic dysregulation observed during disease progression in PCa. We present the first instance of KMT2C mutation within the blood of Brazilian PCa patients. Furthermore, out of the recognized variants within the KMT2C gene, 7 were designated as deleterious. Thirteen deleterious variants were exclusively detected in the younger group, while the older group exhibited 37 variants. Within these findings, 4 novel variants emerged, including 1 designated as pathogenic.[Conclusions]: Our findings contribute to a deeper understanding of the genetic factors associated with PCa susceptibility in different age groups, especially among the Brazilian population. This is the first investigation to explore germline variants specifically in younger Brazilian PCa patients, with high relevance given the genetic diversity of the population in Brazil. Additionally, our work presents evidence of functionally deleterious germline variants within the KMT2C gene among Brazilian PCa patients. The identification of novel and functionally significant variants in the KMT2C gene emphasizes its potential role in PCa development and warrants further investigation.The work was supported by an Inova Grant from Fundação Oswaldo Cruz (Fiocruz) (VPPCB-007-FIO-18-2-20) and a PROEP Grant from Conselho Nacional de Pesquisa (CNPq) (442358/2019-9). KBCAC was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).Peer reviewe

Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein–protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation

Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein–protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation