Search

Your search keyword '"Basilico, C"' showing total 482 results
Start Over Author "Basilico, C"
482 results on '"Basilico, C"'

101. DNA sequence requirements for replication of polyomavirus DNA in vivo and in vitro

Author

Prives, C, Murakami, Y, Kern, F G, Folk, W, Basilico, C, and Hurwitz, J

Abstract

Cell extracts of FM3A mouse cells replicate polyomavirus (Py) DNA in the presence of immunoaffinity-purified Py large T antigen, deoxynucleoside triphosphates, ATP, and an ATP-generating system. This system was used to examine the effects of mutations within or adjacent to the Py core origin (ori) region in vitro. The analysis of plasmid DNAs containing deletions within the early-gene side of the Py core ori indicated that sequences between nucleotides 41 and 57 define the early boundary of Py DNA replication in vitro. This is consistent with previously published studies on the early-region sequence requirements for Py replication in vivo. Deleting portions of the T-antigen high-affinity binding sites A and B (between nucleotides 57 and 146) on the early-gene side of the core ori led to increased levels of replication in vitro and to normal levels of replication in vivo. Point mutations within the core ori region that abolish Py DNA replication in vivo also reduced replication in vitro. A mutant with a reversed orientation of the Py core ori region replicated in vitro, but to a lesser extent that wild-type Py DNA. Plasmids with deletions on the late-gene side of the core ori, within the enhancer region, that either greatly reduced or virtually abolished Py DNA replication in vivo replicated to levels similar to those of wild-type Py DNA plasmids in vitro. Thus, as has been observed with simian virus 40, DNA sequences needed for Py replication in vivo are different from and more stringent than those required in vitro.

Published
1987
Full Text
View/download PDF

102. Common regulatory elements control gene expression from polyoma early and late promoters in cells transformed by chimeric plasmids

Author

Kern, F G, Dailey, L, and Basilico, C

Abstract

In a previous report we showed that transcripts initiating from the late promoter of integrated polyoma plasmids could be detected at significant levels when neomycin resistance (neo) coding sequences were linked to this promoter. In this report we used chimeric plasmids that contain either a limited portion of the polyoma genome or deletions within the polyoma noncoding regulatory region to determine the sequence requirements for late promoter activity in this system. We observed no absolute requirement for either the polyoma early coding region or the origin of DNA replication for Neo-r colony formation. We were therefore able to independently assess the effects of deletions in the polyoma enhancer region on gene activity in both the early and late directions. We measured the ability of cells transfected with plasmids containing deletions in this region to form colonies in either semisolid or G418-containing medium under nonreplicative conditions. Our results indicate that either the PvuII 4 fragment, which contains the simian virus 40 core enhancer sequence, or a region from nucleotides 5099 to 5142, which contains the adenovirus type 5 E1A core enhancer sequence, can be deleted without significantly affecting gene expression in either direction. However, a deletion of nucleotides 5099 to 5172 reduced activities to similar extents in both directions, and a plasmid containing a larger deletion of nucleotides 5055 to 5182 showed a further reduction in activity. Although having no effect by itself, a second origin region deletion of nucleotides 5246 to 127 when present in these mutant backgrounds caused either a further reduction or elimination, respectively, of both G418 and agar colony-forming ability, suggesting the presence of an additional common regulatory element within this region. A comparison of 5' ends of neo transcripts present in cells transformed by these plasmids suggested that the reduction in activity was due to deletion of regulatory rather than structural elements of the late promoter. Our results indicate that the noncoding region of polyoma contains multiple complementing regulatory elements that control the level of both early and late gene expression.

Published
1985
Full Text
View/download PDF

103. Transcription from the polyoma late promoter in cells stably transformed by chimeric plasmids

Author

Kern, F G and Basilico, C

Abstract

We have examined the expression of chimeric plasmids containing coding sequences for the herpes simplex virus thymidine kinase (tk) gene or the Tn5 gene for neomycin resistance (neo) linked to the late promoter of polyoma DNA. Although polyoma late genes are generally not expressed in transformed cells containing only integrated viral DNA molecules, rat tk- or wild-type cells transfected with the tk- or neo-containing plasmids were capable of growing in medium containing either hypoxanthine-aminopterin-thymidine or G418, respectively, under conditions nonpermissive for extrachromosomal DNA replication, indicating that the tk or neo genes were fully expressed. Moreover, cells were capable of growth in either hypoxanthine-aminopterin-thymidine or G418, even in the absence of direct selection for this activity. Northern analysis indicated steady-state levels of tk or neo transcripts that approximated the levels of polyoma early transcripts. S1 analysis showed that these transcripts initiated within the late promoter of polyoma and that their 5' ends mapped at positions similar or identical to those utilized during late lytic infection. The effect of substitution of polyadenylation signals was examined. Although plasmids containing the polyoma early polyadenylation signal were more efficient in conferring to cells a stable G418-resistant phenotype than similar constructions using the late signal, both signals were found to be effectively utilized. This indicates that the inability to detect late transcripts in polyoma-transformed cells in the absence of free viral DNA production is not an effect of inefficient mRNA cleavage or polyadenylation. Our results suggest that late gene expression in integrated polyoma genomes is not regulated at the level of message initiation but, most likely, through posttranscriptional events.

Published
1985
Full Text
View/download PDF

104. Cell transformation mediated by chromosomal deoxyribonucleic acid of polyoma virus-transformed cells

Author

Della Valle, G, Fenton, R G, and Basilico, C

Abstract

To study the mechanism of deoxyribonucleic acid (DNA)-mediated gene transfer, normal rat cells were transfected with total cellular DNA extracted from polyoma virus-transformed cells. This resulted in the appearance of the transformed phenotype in 1 X 10(-6) to 3 X 10(-6) of the transfected cells. Transformation was invariably associated with the acquisition of integrated viral DNA sequences characteristic of the donor DNA. This was caused not by the integration of free DNA molecules, but by the transfer of large DNA fragments (10 to 20 kilobases) containing linked cellular and viral sequences. Although Southern blot analysis showed that integration did not appear to occur in a homologous region of the recipient chromosome, the frequency of transformation was rather high when compared with that of purified polyoma DNA, perhaps due to "position" effects or to the high efficiency of recombination of large DNA fragments.

Published
1981
Full Text
View/download PDF

105. A reiterated leader sequence is present in polyomavirus late transcripts produced by a transformed rat cell line

Author

Kern, F G, Bovi, P D, and Basilico, C

Abstract

In cells transformed by polyomavirus, the viral genome is integrated into the host DNA, and in the absence of excision, viral gene expression is limited to the early region. We report here that the ability of a unique transformed rat cell line, designated SS1A, to produce readily detectable levels of late mRNAs is due to rearrangements of the integrated viral sequences. The structure of the SS1A insertion, resulting from amplification and deletion events, allows for the formation of a primary late transcript that can subsequently be spliced to generate a reiterated leader attached to the body of the late mRNA coding sequences. The presence of transcripts containing such a leader was confirmed by sequencing the 5' end of cDNA copies of late mRNAs isolated from a library constructed with SS1A mRNA. These results suggest that a reiterated leader sequence is necessary to stabilize late mRNA.

Published
1987
Full Text
View/download PDF

106. A subclass of polyomavirus middle tumor antigen binds to DNA cellulose

Author

Bolen, J B, Cary, K, Scheller, A, Basilico, C, Israel, M A, and Prives, C

Abstract

We examined the binding of polyomavirus large (L-T)-, middle (M-T)-, and small-tumor antigens to DNA cellulose. At pH 6.0, the majority of L-T bound to calf thymus DNA cellulose, while little or no small tumor antigen was retained under these conditions. Unexpectedly, a small but reproducible proportion of M-T bound to both native and denatured DNA cellulose. M-T encoded by polyomavirus mutant dl 8, which expressed shortened L-T and M-T, bound to DNA, indicating that the deleted sequences are not required for DNA binding. Also, M-T from transformed BMT-1 rat cells, which synthesize exclusively this polyomavirus tumor antigen, bound to DNA, indicating that its binding is not due to association with other polyomavirus-encoded proteins. Using the DNA fragment immunoassay, we found that, under conditions in which L-T bound specifically to DNA fragments containing viral regulatory sequences, no viral DNA fragments were bound by M-T. The existence of distinct subpopulations of M-T that differ in their DNA-binding properties was indicated by rebinding experiments in which M-T that had bound to DNA cellulose rebound very efficiently, while that which had not been originally retained by DNA cellulose rebound poorly. Furthermore, the M-T-pp60 c-src complex did not bind to DNA cellulose. These data suggest that polyomavirus M-T is heterogeneous, consisting of populations of molecules that differ in their interactions with DNA cellulose.

Published
1986
Full Text
View/download PDF

107. Regulation of polyomavirus late promoter activity by viral early proteins

Author

Kern, F G, Pellegrini, S, Cowie, A, and Basilico, C

Abstract

To assess the effect of the polyomavirus (Py) early proteins, the large T (LT), middle T (MT), and small T (ST) antigens, on gene expression from the Py late promoter, replication-defective plasmid constructs with the bacterial chloramphenicol acetyltransferase (cat) gene linked to this promoter were cotransfected into mouse or rat cells with plasmids capable of producing either LT, MT, or all three early proteins. When target CAT plasmids contained a truncated early region and thus had the coding potential for MT and ST, base-line CAT activities were low, whereas cotransfection with an LT plasmid resulted in up to 70-fold stimulation of CAT activity that was also reflected in similar increases in the level of steady-state mRNA. Studies with target plasmids with deletions within the Py regulatory region indicated that at least the major LT-binding site C and a functional enhancer region were both required for maximal stimulation of CAT activity. However, although enhancer deletions totally suppressed the ability of target plasmids to be trans activated, a consistent two- to fourfold stimulation of CAT activity by LT was still observed with a plasmid in which all three major LT-binding sites were deleted. Of four mutant LTs incapable of binding Py DNA but retaining immortalization potential, only one showed a low but significant trans-activating ability. When the early coding region was completely eliminated from the target plasmid, base-line CAT activity was increased 10-fold. LT failed to stimulate CAT activity to the same levels observed with target plasmid containing the truncated early region, but this limited response could be enhanced by supplying, in addition, MT and ST. Our results suggest that LT trans activation may involve the formation of a complex of transcriptional factors which interacts with the enhancer, an interaction that is facilitated both by the binding of LT to the Py regulatory region and by the presence of MT or ST or both, and that a significant portion of LT stimulation of late gene expression is a result of the removal of the competing early transcriptional unit via autoregulation. In addition, our results suggest that LT trans activation involves a second indirect component acting independently of LT binding and that the immortalization and trans activation functions of LT can be dissociated.

Published
1986
Full Text
View/download PDF

108. Sequences in the polyomavirus DNA regulatory region involved in viral DNA replication and early gene expression

Author

Dailey, L and Basilico, C

Abstract

We constructed and analyzed a series of deletion mutants in the noncoding regulatory region of tsa polyomavirus DNA to identify some of the sequences critical to the DNA replication origin and to the expression of the viral early genes in vivo. By using both transient and long-term assays under conditions where the influence of large T antigen (T-Ag) in replication or autoregulation was minimized, we observed no more than a 30% reduction in early gene expression upon removal of the CAAT or TATA elements or both. These assays demonstrated a predominant effect of upstream promoter or enhancer elements and indicated that removal of the CAAT or TATA boxes did not significantly affect viral early gene expression. Studies on the replicative ability of these mutants in mouse cells constitutively expressing the polyoma early proteins revealed that the removal of DNA sequences contained within a previously identified T-Ag high-affinity binding site (nucleotides 39 to 64) abolished viral DNA replication, whereas removal of two other high-affinity sites, closer to the early mRNA cap sites, did not. Furthermore, a deletion including this same high-affinity site plus a low-affinity binding site within the 32-base-pair palindrome of the origin core sequences eliminated the ability of the viral large T-Ag to efficiently repress early gene transcription. It is thus possible that the origin-proximal high-affinity T-Ag binding site is involved in both of the functions of large T-Ag, i.e., the initiation of viral DNA replication and the autoregulation of early gene transcription.

Published
1985
Full Text
View/download PDF

109. Relationship between integrated and nonintegrated viral DNA in rat cells transformed by polyoma virus

Author

Gattoni, S, Colantuoni, V, and Basilico, C

Abstract

Fischer rat fibroblasts transformed by polyoma virus contain, in addition to viral sequences integrated into the host genome, nonintegrated viral DNA molecules, whose presence is under the control of the viral A gene. To understand the mechanism of production of the "free" viral DNA, we have characterized the DNA species produced by several rat lines transformed by wild-type virus or by ts-a polyoma virus and compared them with the integrated viral sequences. Every cell line tested yielded a characteristic number of discrete species of viral DNA. The presence of defectives was a very common occurrence, and these molecules generally carried deletions mapping in the viral "late" region. The production of multiple species of free viral DNA was not due to heterogeneity of the transformed rat cell population, and its pattern did not change upon fusion with permissive mouse cells. Analysis of the integrated viral DNA sequences in the same cell lines showed, in most cases, a full head-to-tail tandem arrangement of normal-size and defective molecules. The free DNA produced by these lines faithfully reflected the integrated species. This was true also in the case of a cell line which contained a viral insertion corresponding to approximately 1.3 polyoma genomes, with each of the repeated portions of the viral DNA molecule carrying a different-size deletion. These results support the hypothesis that the free DNA derives from the integrated form through a mechanism of homologous recombination leading to excision and limited replication.

Published
1980
Full Text
View/download PDF

110. State of the viral DNA in rat cells transformed by polyma virus. II. Identification of the cells containing nonintegrated viral DNA and the effect of viral mutations

Author

Zouzias, D, Prasad, I, and Basilico, C

Abstract

F2408 rat cells transformed by polyoma virus contained integrated and nonintegrated viral DNA. The presence of nonintegrated viral DNA is under control of the A early viral function. Polyoma ts-a-transformed rat cells lose the free viral DNA when growth at the nonpermissive temperature (40 degrees C), but they reexpress it 1 to 3 days after they are shifted back to the permissive temperature. In contrast, rat cells transformed by a late viral mutant, ts-8, contain free viral DNA at both permissive and nonpermissive temperatures. Treatment of the transformed rat cells with mitomycin C produces a large increase in the quantity of free viral DNA and some production of infectious virus. Experiments of in situ hybridization, with 3H-labeled polyoma complementary RNA as a probe, show that only a minority (approximately 0.1%) of the transformed cells contain nonintegrated viral DNA at any given time. These results suggest that the presence of free viral DNA in polyoma-transformed rat cells is caused by a spontaneous induction of viral DNA replication, occurring with low but constant probability in the transformed cell population, and that the free viral DNA molecules originate from the integrated ones, probably through a phenomenon of excision and limited replication.

Published
1977
Full Text
View/download PDF

112. Organization and expression of the cell cycle gene, ts11, that encodes asparagine synthetase

Author

Greco, A, Gong, S S, Ittmann, M, and Basilico, C

Abstract

The human ts11 gene was isolated on the basis of its ability to complement the mutation of the BHK cell cycle ts11 mutant, which is blocked in G1 at the nonpermissive temperature. This gene has now been identified as the structural gene for asparagine synthetase (AS) on the bases of sequence homology and the ability of exogenous asparagine to bypass the ts11 block. The ts11 (AS) mRNA has a size of about 2 kilobases and is induced in mid-G1 phase in human, mouse, and hamster cell lines. We have studied the organization and regulation of expression of the ts11 gene. The human ts11 gene consists of 13 exons (the first two noncoding) interspersed in a region of about 21 kilobases of DNA. Transient expression assays using the bacterial chloramphenicol acetyltransferase reporter gene identified two separate promoters: one (ts11 P1) contained in a 280-base-pair region upstream of the first exon and the other (ts11 P2) contained in the first intron. ts11 P1 produced about sixfold more chloramphenicol acetyltransferase activity than did ts11 P2 and had features of the promoters of housekeeping genes: high G + C content, multiple transcription start sites, absence of a TATA box, and presence of putative Sp1 binding sites. ts11 P2 contained a TATA sequence and other elements characteristic of a promoter, but so far we have no evidence of its physiological utilization. The ts11 gene was overexpressed in ts11 cells exposed to the nonpermissive temperature. Addition of asparagine to the culture medium led to a drastic decrease in mRNA levels and prevented G1 induction in serum-stimulated cells, which indicated that expression of the AS gene is regulated by a mechanism of end product inhibition.

Published
1989
Full Text
View/download PDF

114. OUTCOMES OF RELAPSED OR REFRACTORY AND NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA AFTER HYPOMETHYLATING AGENT AND VENETOCLAX. THE ITALIAN REAL-LIFE EXPERIENCE BEFORE PUBLIC HEALTH REIMBURSEMENT (AVALON STUDY)

Author

Todisco, E., CRISTINA PAPAYANNIDIS, Fracchiolla, N., Cerchione, C., Marconi, G., Petracci, E., Zingaretti, C., Vetro, C., Martelli, M. P., Zappasodi, P., Di Renzo, N., Cignetti, A., Lussana, F., Mattei, D., Ciceri, F., Facchini, L., Selleri, C., Fumagalli, M., Audisio, E., Griguolo, D., Basilico, C., Manfra, I., Borlenghi, E., Cairoli, R., Salutari, P., Gottardi, M., Molteni, A., Martini, V., Lunghi, M., Fianchi, L., Cilloni, D., Lanza, F., Abruzzese, E., Cascavilla, N., Rivellini, F., Ferrara, F., Maurillo, L., Nanni, J., Romano, A., Cardinali, V., Gigli, F., Vincenzo, F., Volpi, R., Sciume, M., Tarella, C., Rossi, G., Martinelli, G., Todisco, E, Papayannidis, C, Fracchiolla, N, Cerchione, C, Marconi, G, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Cignetti, A, Lussana, F, Mattei, D, Ciceri, F, Facchini, L, Selleri, C, Fumagalli, M, Audisio, E, Griguolo, D, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Vincenzo, F, Volpi, R, Sciume, M, Tarella, C, Rossi, G, and Martinelli, G

Subjects
Hematology

119. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America

Author

Costagliola, D., Dabis, F., Monforte, Ad, Wolf, F., Egger, M., Fatkenheuer, G., Gill, J., Hogg, R., Justice, A., Ledergerber, B., Lundgren, J., May, M., Phillips, A., Reiss, P., Sabin, C., Staszewski, S., Sterne, J., Weller, I., Beckthold, B., Yip, B., Dauer, B., Fusco, J., Grabar, S., Lanoy, E., Junghans, C., Lavignolle, V., Leth, F., Pereira, E., Pezzotti, P., Schmeisser, N., Billaud, E., Boue, F., Duval, X., Duvivier, C., Enel, P., Fournier, S., Gasnault, J., Gaud, C., Gilquin, J., Khuong, Ma, Lang, Jm, Mary-Krause, M., Matheron, S., Meyohas, Mc, Pialoux, G., Poizot-Martin, I., Pradier, C., Rouveix, E., Salmon-Ceron, D., Sobel, A., Tattevin, P., Tissot-Dupont, H., Yasdanpanah, Y., Aronica, E., Tirard-Fleury, V., Tortay, I., Abgrall, S., Guiguet, M., Leneman, H., Lievre, L., Potard, V., Saidi, S., Vilde, Jl, Leport, C., Yeni, P., Bouvet, E., Gaudebout, C., Crickx, B., Picard-Dahan, C., Weiss, L., Tisne-Dessus, D., Sicard, D., Salmon, D., Auperin, I., Viard, Jp, Roudiere, L., Delfraissy, Jf, Goujard, C., Lesprit, P., Jung, C., Meynard, Jl, Picard, O., Desplanque, N., Cadranel, J., Mayaud, C., Rozenbaum, W., Bricaire, F., Katlama, C., Herson, S., Simon, A., Decazes, Jm, Molina, Jm, Clauvel, Jp, Gerard, L., Widal, Ghlf, Sellier, P., Diemer, M., Dupont, C., Berthe, H., Saiag, P., Mortier, L., Mortier, E., Chandemerle, C., Truchis, P., Bentata, M., Honore, P., Tassi, S., Jeantils, V., Mechali, D., Taverne, B., Laurichesse, H., Gourdon, F., Lucht, F., Fresard, A., Faller, Jp, Eglinger, P., Bazin, C., Verdon, R., Peyramond, D., Boibieux, A., Touraine, Jl, Livrozet, Jm, Trepo, C., Cotte, L., Ravaux, I., Delmont, Jp, Moreau, J., Gastaut, Ja, Soubeyrand, J., Retornaz, F., Blanc, Pa, Allegre, T., Galinier, A., Ruiz, Jm, Lepeu, G., Granet-Brunello, P., Pelissier, L., Esterni, Jp, Nezri, M., Cohen-Valensi, R., Laffeuillade, A., Chadapaud, S., Reynes, J., May, T., Rabaud, C., Raffi, F., Pugliese, P., Michelet, C., Arvieux, C., Caron, F., Borsa-Lebas, F., Fraisse, P., Massip, P., Cuzin, L., Arlet-Suau, E., Legrand, Mft, Sobesky, M., Pradinaud, R., Guyon, F., Contant, M., Montroni, M., Scalise, G., Braschi, Mc, Aviano, Ar, Tirelli, U., Cinelli, R., Pastore, G., Ladisa, N., Minafra, G., Suter, F., Arici, C., Chiodo, F., Colangeli, V., Fiorini, C., Coronado, O., Carosi, G., Cadeo, Gp, Torti, C., Minardi, C., Bertelli, D., Rizzardini, G., Melzi, S., Manconi, Pe, Catanzaro, Pp, Cosco, L., Scerbo, A., Vecchiet, J., D Alessandro, M., Santoro, D., Pusterla, L., Carnevale, G., Citterio, P., Vigano, P., Mena, M., Ghinelli, F., Sighinolfi, L., Leoncini, F., Mazzotta, F., Pozzi, M., Lo Caputo, S., Angarano, G., Grisorio, B., Saracino, A., Ferrara, S., Grima, P., Tundo, P., Pagano, G., Cassola, G., Alessandrini, A., Piscopo, R., Toti, M., Chigiotti, S., Soscia, F., Tacconi, L., Orani, A., Perini, P., Scasso, A., Vincenti, A., Chiodera, F., Castelli, P., Scalzini, A., Palvarini, L., Moroni, M., Lazzarin, A., Cargnel, A., Vigevani, Gm, Caggese, L., Repetto, D., Galli, A., Merli, S., Pastecchia, C., Moioli, Mc, Esposito, R., Mussini, C., Abrescia, N., Chirianni, A., Izzo, Cm, Piazza, M., Marco, M., Viglietti, R., Manzillo, E., Nappa, S., Colomba, A., Abbadessa, V., Prestileo, T., Mancuso, S., Ferrari, C., Pizzaferri, P., Filice, G., Minoli, L., Bruno, R., Novati, S., Baldelli, F., Tinca, M., Petrelli, E., Cioppi, A., Alberici, F., Ruggieri, A., Menichetti, F., Martinelli, C., Stefano, C., La Gala, A., Ballardini, G., Rizzo, E., Magnani, G., Ursitti, Ma, Arlotti, M., Ortolani, P., Cauda, R., Dianzani, F., Ippolito, G., Antinori, A., Antonucci, G., D Elia, S., Narciso, P., Petrosillo, N., Vullo, V., Luca, A., Bacarelli, A., Zaccarelli, M., Acinapura, R., Longis, P., Brandi, A., Trotta, Mp, Noto, P., Lichtner, M., Capobianchi, MR, Carletti, F., Girardi, E., Rezza, G., Mura, Ms, Mannazzu, M., Caramello, P., Di Perri, G., Soranzo, Ml, Orofino, Gc, Arnaudo, I., Bonasso, M., Grossi, Pa, Basilico, C., Poggio, A., Bottari, G., Raise, E., Ebo, F., Lalla, F., Tositti, G., Resta, F., Loso, K., Lepri, Ac, Battegay, M., Bernasconi, E., Boni, J., Bucher, H., Burgisser, P., Cattacin, S., Cavassini, M., Dubs, R., Elzi, L., Erb, P., Fantelli, K., Fischer, M., Flepp, M., Fontana, A., Francioli, P., Furrer, H., Gorgievski, M., Hirschel, B., Kaiser, L., Kind, C., Klimkait, T., Lauper, U., Opravil, M., Paccaud, F., Pantaleo, G., Perrin, L., Piffaretti, Jc, Rickenbach, M., Rudin, C., Schmid, P., Schupbach, J., Speck, R., Telenti, A., Trkola, A., Vernazza, P., Weber, R., Yerly, S., Bronsveld, W., Hillebrand-Haverkort, Me, Prins, Jm, Bos, Jc, Schattenkerk, Jkme, Geerlings, Se, Godfried, Mh, Lange, Jma, Leth, Fc, Lowe, Sh, Meer, Jtm, Nellen, Fjb, Pogany, K., Poll, T., Ruys, Ta, Sankatsing, S., Steingrover, R., Twillert, G., Valk, M., Vonderen, Mga, Vrouenraets, Sme, Vugt, M., Wit, Fwmn, Kuijpers, Tw, Pajkrt, D., Scherpbier, Hj, Eeden, A., Ten Veen, Jh, Dam, Ps, Roos, Jc, Brinkman, K., Frissen, Phj, Weigel, Hm, Mulder, Jw, Gorp, Ecm, Meenhorst, Pl, Mairuhu, Ata, Ziekenhuis, S., Veenstra, J., Danner, Sa, Agtmael, Ma, Claessen, Fap, Perenboom, Rm, Rijkeboer, A., Vonderen, M., Richter, C., Berg, J., Leusen, R., Vriesendorp, R., Jeurissen, Fjf, Kauffmann, Rh, Koger, Elw, Bravenboer, B., Ten Napel, Chh, Kootstra, Gj, Sprenger, Hg, Miesen, Wmaj, Doedens, R., Scholvinck, Eh, Ten Kate, Rw, Houte, Dpf, Polee, M., Kroon, Fp, van den Broek, Dissel, Jt, Schippers, Ef, Schreij, G., Geest, Sv, Verbon, A., Koopmans, Pp, Keuter, M., Post, F., Ven, Ajam, Ende, Me, Gyssens, Ic, Feltz, M., Den Hollander, Jg, Marie, S., Nouwen, Jl, Rijnders, Bja, Vries, Tems, Driessen, G., Groot, R., Hartwig, N., Juttmann, Jr, Heul, C., Kasteren, Mee, Schneider, Mme, Bonten, Mjm, Borleffs, Jcc, Ellerbroek, Pm, Hoepelman, Im, Jaspers, Cajj, Schouten, I., Schurink, Cam, Geelen, Spm, Wolfs, Tfw, Blok, Wl, Tanis, Aa, Groeneveld, Php, Klinieken-Zwolle, I., Back, Nkt, Bakker, Meg, Berkhout, B., Jurriaans, S., Cuijpers, T., Rietra, Pjgm, Roozendaal, Kj, Pauw, W., Zanten, Ap, Blomberg, Bme, Savelkoul, P., Swanink, Cma, Franck, Pfh, Lampe, As, Hendriks, R., Schirm, J., Veenendaal, D., Storm, H., Weel, J., Zeijl, H., Kroes, Acm, Claas, Hcj, Bruggeman, Camva, Goossens, Vj, Galama, Jmd, Melchers, Wjg, Poort, Yag, Doornum, Gjj, Niesters, Mg, Osterhaus, Adme, Schutten, M., Buiting, Agm, Swaans, Cam, Boucher, Cab, Boel, E., Jansz, Af, Losso, M., Duran, A., Vetter, N., Karpov, I., Vassilenko, A., Clumeck, N., Wit, S., Poll, B., Colebunders, R., Machala, L., Rozsypal, H., Dalibor Sedlacek, Nielsen, J., Benfield, T., Kirk, O., Gerstoft, J., Katzenstein, T., Hansen, Abe, Skinhoj, P., Pedersen, C., Zilmer, K., Girard, Pm, Saint-Marc, T., Vanhems, P., Dietrich, M., Manegold, C., Lunzen, J., Stellbrink, Hj, Bickel, M., Goebel, Fd, Rockstroh, J., Schmidt, R., Kosmidis, J., Gargalianos, P., Sambatakou, H., Perdios, J., Panos, G., Filandras, A., Karabatsaki, E., Banhegyi, D., Mulcahy, F., Yust, I., Turner, D., Burke, M., Pollack, S., Hassoun, G., Sthoeger, Z., Maayan, S., Chiesi, A., Borghi, R., Pristera, R., Gabbuti, A., Montesarchio, E., Iacomi, F., Finazzi, R., Viksna, L., Chaplinskas, S., Hemmer, R., Staub, T., Bruun, J., Maeland, A., Ormaasen, V., Knysz, B., Gasiorowski, J., Horban, A., Prokopowicz, D., Wiercinska-Drapalo, A., Boron-Kaczmarska, A., Pynka, M., Beniowski, M., Mularska, E., Trocha, H., Antunes, F., Valadas, E., Mansinho, K., Matez, F., Duiculescu, D., Babes, V., Streinu-Cercel, A., Vinogradova, E., Rakhmanova, A., Jevtovic, D., Mokras, M., Stanekova, D., Gonzalez-Lahoz, J., Sanchez-Conde, M., Garcia-Benayas, T., Martin-Carbonero, L., Soriano, V., Clotet, B., Jou, A., Conejero, J., Tural, C., Gatell, Jm, Miro, Jm, Blaxhult, A., Karlsson, A., Pehrson, P., Soravia-Dunand, V., Kravchenko, E., Chentsova, N., Barton, S., Johnson, Am, Mercey, D., Johnson, Ma, Mocroft, A., Murphy, M., Weber, J., Scullard, G., Fisher, M., Brettle, R., Loveday, C., Gatell, J., Johnson, A., Vella, S., Gjorup, I., Friis-Moeller, N., Cozzi-Lepri, A., Bannister, W., Mollerup, D., Podlevkareva, D., Olsen, Ch, Kjaer, J., Raffanti, S., Dieterch, D., Becker, S., Scarsella, A., Fusco, G., Most, B., Balu, R., Rana, R., Beckerman, R., Ising, T., Irek, R., Johnson, B., Hirani, A., Dejesus, E., Pierone, G., Lackey, P., Irek, C., Burdick, J., Leon, S., Arch, J., Helm, Eb, Carlebach, A., Muller, A., Haberl, A., Nisius, G., Lennemann, T., Rottmann, C., Wolf, T., Stephan, C., Mosch, M., Gute, P., Locher, L., Lutz, T., Klauke, S., Knecht, G., Doerr, Hw, Sturmer, M., Hentig, N., Jennings, B., Beylot, J., Chene, G., Dupon, M., Longy-Boursier, M., Pellegrin, Jl, Ragnaud, Jm, Salamon, R., Thiebaut, R., Lewden, C., Lawson-Ayayi, S., Mercie, P., Moreau, Jf, Moriat, P., Bernard, N., Lacoste, D., Malvy, D., Neau, D., Blaizeau, Mj, Decoin, M., Delveaux, S., Hannapier, C., Labarrere, S., Lavignolle-Aurillac, V., Uwamaliya-Nziyumvira, B., Palmer, G., Touchard, D., Balestre, E., Alioum, A., Jacqmin-Gadda, H., Morlat, P., Bonarek, M., Bonnet, F., Coadou, B., Gellie, P., Nouts, C., Bocquentin, F., Dutronc, H., Lafarie, S., Aslan, A., Pistonne, T., Thibaut, P., Vatan, R., Chambon, D., La Taille, C., Cazorla, C., Ocho, A., Castera, L., Fleury, H., Lafon, Me, Masquelier, B., Pellegrin, I., Breilh, D., Blanco, P., Loste, P., Caunegre, L., Bonnal, F., Farbos, S., Ferrand, M., Ceccaldi, J., Tchamgoue, S., Witte, S., Buy, E., Alexander, C., Barrios, R., Braitstein, P., Brumme, Z., Chan, K., Cote, H., Gataric, N., Geller, J., Guillemi, S., Harrigan, Harris, M., Joy, R., Levy, A., Montaner, J., Montessori, V., Palepu, A., Phillips, E., Phillips, P., Press, N., Tyndall, M., Wood, E., Ballinger, J., Bhagani, S., Breen, R., Byrne, P., Carroll, A., Cropley, I., Cuthbertson, Z., Drinkwater, T., Fernandez, T., Geretti, Am, Murphy, G., Ivens, D., Johnson, M., Kinloch-De Loes, S., Lipman, M., Madge, S., Prinz, B., Bell, Dr, Shah, S., Swaden, L., Tyrer, M., Youle, M., Chaloner, C., Gumley, H., Holloway, J., Puradiredja, D., Sweeney, J., Tsintas, R., Bansi, L., Fox, Z., Lampe, F., Smith, C., Amoah, E., Clewley, G., Dann, L., Gregory, B., Jani, I., Janossy, G., Kahan, M., Thomas, M., Gill, Mj, Read, R., Schmeisser, V., Voigt, K., Wasmuth, Jc, Wohrmann, A., and Antiretroviral Therapy Cohort Coll

120. Fibroblast growth factor 2 promotes tumor progression in an autochthonous mouse model of prostate cancer

Author

Polnaszek, N., Kwabi-Addo, B., Leif Peterson, Ozen, M., Greenberg, N. M., Ortega, S., Basilico, C., and Ittmann, M.

Subjects
Male, Mice, Knockout, Vascular Endothelial Growth Factor A, Prostatic Neoplasms, Cell Differentiation, Up-Regulation, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Disease Models, Animal, Mice, Disease Progression, Animals, Fibroblast Growth Factor 1, Female, Fibroblast Growth Factor 2, Gene Silencing, Alleles, Oligonucleotide Array Sequence Analysis
Abstract

Fibroblast growth factor (FGF) 2 (or basic FGF) is expressed at increased levels in human prostate cancer. FGF2 can promote cell motility and proliferation, increase tumor angiogenesis, and inhibit apoptosis, all of which play an important role in tumor progression. To determine whether FGF2 plays a critical role in prostate cancer progression, we have used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model system. A high percentage of TRAMP mice develop metastatic prostate cancer, and thus the TRAMP model is useful for evaluating cancer progression. TRAMP mice were crossed with FGF2 knockout (FGF2(-/-)) mice, and tumor progression in TRAMP mice that were either hemi- or homozygous for inactivation of the FGF2 allele was compared with progression in wild-type TRAMP mice. Inactivation of even one FGF2 allele resulted in increased survival, a decrease in metastasis, and inhibition of progression to the poorly differentiated phenotype in primary prostatic tumors. When compared with wild-type mice, poorly differentiated tumors arising in FGF(+/-) and FGF(-/-) mice expressed higher levels of vascular endothelial growth factor and, in some cases, increased levels of acidic FGF intracellular binding protein, a nuclear FGF1-binding protein. These findings suggest that both FGF2-mediated angiogenesis and intranuclear FGF2 activities may promote tumor progression and support the hypothesis that FGF2 plays a significant role in prostate cancer progression in vivo.

121. CLINICAL CHARACTERISTICS AND OUTCOME OF INVASIVE INFECTIONS DUE TO SAPROCHAETE SPECIES IN PATIENTS AFFECTED BY HEMATOLOGICAL MALIGNANCIES. A MULTI-CENTER STUDY ON BEHALF OF SEIFEM/FUNGISCOPE REGISTRY

Author

Del Principe, M. I., Criscuolo, M., Seidel, D., Dargenio, M., Racil, Z., Piedimonte, M., Marchesi, F., Nadali, G., Koehler, P., Fracchiolla, N., Cattaneo, C., Klimko, N., Spolzino, A., Karapinar, D. Yilmaz, Demiraslan, H., Duarte, R., Demeter, J., Stanziani, M., Melillo, L., Basilico, C. M., Cesaro, S., Paterno, G., Oliver Cornely, Califano, C., Delia, M., Busca, A., and Pagano, L.

137. AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia

Author

Todisco, Elisabetta, Papayannidis, Cristina, Fracchiolla, Nicola, Petracci, Elisabetta, Zingaretti, Chiara, Vetro, Calogero, Martelli, Maria Paola, Zappasodi, Patrizia, Di Renzo, Nicola, Gallo, Susanna, Audisio, Ernesta, Griguolo, Davide, Cerchione, Claudio, Selleri, Carmine, Mattei, Daniele, Bernardi, Massimo, Fumagalli, Monica, Rizzuto, Giuliana, Facchini, Luca, Basilico, Claudia Maria, Manfra, Ilenia, Borlenghi, Erika, Cairoli, Roberto, Salutari, Prassede, Gottardi, Michele, Molteni, Alfredo, Martini, Vincenza, Lunghi, Monia, Fianchi, Luana, Cilloni, Daniela, Lanza, Francesco, Abruzzese, Elisabetta, Cascavilla, Nicola, Rivellini, Flavia, Ferrara, Felicetto, Maurillo, Luca, Nanni, Jacopo, Romano, Alessandra, Cardinali, Valeria, Gigli, Federica, Roncoroni, Elisa, Federico, Vincenzo, Marconi, Giovanni, Volpi, Roberta, Sciumè, Mariarita, Tarella, Corrado, Rossi, Giuseppe, Martinelli, Giovanni, Todisco, Elisabetta, Papayannidis, Cristina, Fracchiolla, Nicola, Petracci, Elisabetta, Zingaretti, Chiara, Vetro, Calogero, Martelli, Maria Paola, Zappasodi, Patrizia, Di Renzo, Nicola, Gallo, Susanna, Audisio, Ernesta, Griguolo, Davide, Cerchione, Claudio, Selleri, Carmine, Mattei, Daniele, Bernardi, Massimo, Fumagalli, Monica, Rizzuto, Giuliana, Facchini, Luca, Basilico, Claudia Maria, Manfra, Ilenia, Borlenghi, Erika, Cairoli, Roberto, Salutari, Prassede, Gottardi, Michele, Molteni, Alfredo, Martini, Vincenza, Lunghi, Monia, Fianchi, Luana, Cilloni, Daniela, Lanza, Francesco, Abruzzese, Elisabetta, Cascavilla, Nicola, Rivellini, Flavia, Ferrara, Felicetto, Maurillo, Luca, Nanni, Jacopo, Romano, Alessandra, Cardinali, Valeria, Gigli, Federica, Roncoroni, Elisa, Federico, Vincenzo, Marconi, Giovanni, Volpi, Roberta, Sciumè, Mariarita, Tarella, Corrado, Rossi, Giuseppe, Martinelli, Giovanni, Todisco, E, Papayannidis, C, Fracchiolla, N, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Gallo, S, Audisio, E, Griguolo, D, Cerchione, C, Selleri, C, Mattei, D, Bernardi, M, Fumagalli, M, Rizzuto, G, Facchini, L, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Roncoroni, E, Federico, V, Marconi, G, Volpi, R, Sciumè, M, Tarella, C, Rossi, G, and Martinelli, G

Subjects
Cancer Research, hypomethylating agents, Oncology, hypomethylating agent, relapsed and refractory AML, venetoclax, real-life data, acute myeloid leukemia
Abstract

Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax+HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60days of therapy. Infections were confirmed as the most common nonhematologic adverse event. Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax+HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax+HMA effectiveness and toxicities in real life.

Published
2023

138. The transcription factor Sox2 is required for osteoblast self-renewal

Author

Claudio Basilico, Upal Basu-Roy, Silvia K. Nicolis, Rebecca Favaro, Davide Ambrosetti, Alka Mansukhani, U. Basu-Roy, Ambrosetti D., Favaro R., Nicolis S.K., Mansukhani A., Basilico C., Basu Roy, U, Ambrosetti, D, Favaro, R, Nicolis, S, Mansukhani, A, and Basilico, C

Subjects
musculoskeletal diseases, Cellular differentiation, Sox2, Embryonic Development, Fibroblast growth factor, Article, Cell Line, Mice, SOX2, stomatognathic system, medicine, Animals, Cell Lineage, animal genetic model, Molecular Biology, transcription factor, Mice, Knockout, Osteoblasts, Activating Transcription Factor 2, biology, SOXB1 Transcription Factors, fungi, Cell Differentiation, Osteoblast, Cell Biology, osteogenesi, Embryonic stem cell, Molecular biology, Activating transcription factor 2, stem cell, medicine.anatomical_structure, Cell culture, embryonic structures, biology.protein, RNA Interference, Stem cell, Signal Transduction
Abstract

The development and maintenance of most tissues and organs require the presence of multipotent and unipotent stem cells that have the ability of self-renewal as well as of generating committed, further differentiated cell types. The transcription factor Sox2 is essential for embryonic development and maintains pluripotency and self-renewal in embryonic stem cells. It is expressed in immature osteoblasts/osteoprogenitors in vitro and in vivo and is induced by fibroblast growth factor signaling, which stimulates osteoblast proliferation and inhibits differentiation. Sox2 overexpression can by itself inhibit osteoblast differentiation. To elucidate its function in the osteoblastic lineage, we generated mice with an osteoblast-specific, Cre-mediated knockout of Sox2. These mice are small and osteopenic, and mosaic for Sox2 inactivation. However, culturing calvarial osteoblasts from the mutant mice for 2-3 passages failed to yield any Sox2-null cells. Inactivation of the Sox2 gene by Cre-mediated excision in cultured osteoblasts showed that Sox2-null cells could not survive repeated passage in culture, could not form colonies, and arrested their growth with a senescent phenotype. In addition, expression of Sox2-specific shRNAs in independent osteoblastic cell lines suppressed their proliferative ability. Osteoblasts capable of forming 'osteospheres' are greatly enriched in Sox2 expression. These data identify a novel function for Sox2 in the maintenance of self-renewal in the osteoblastic lineage.

Published
2010

139. Validation of the 'fitness criteria' for the treatment of older patients with acute myeloid leukemia: A multicenter study on a series of 699 patients by the Network Rete Ematologica Lombarda (REL)

Author

Chiara Pagani, Erika Borlenghi, Matteo Claudio Da Via, Chiara Cattaneo, Fabio Ciceri, Roberto Cairoli, Francesco Passamonti, Massimo Bernardi, Claudia Basilico, Nicola Stefano Fracchiolla, Valentina Mancini, Mauro Turrini, Mariarita Sciumè, Elisabetta Todisco, Giuseppe Rossi, Patrizia Zappasodi, Elisa Cerqui, Margherita Sciumé, Borlenghi, E, Pagani, C, Zappasodi, P, Bernardi, M, Basilico, C, Cairoli, R, Fracchiolla, N, Todisco, E, Turrini, M, Cattaneo, C, Da Via, M, Ciceri, F, Passamonti, F, Mancini, V, Sciume, M, Cerqui, E, and Rossi, G

Subjects
medicine.medical_specialty, Multivariate analysis, Fitne, Concordance, Karyotype, Comorbidity, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Fitness, medicine, Humans, 030212 general & internal medicine, Exercise, Aged, Retrospective Studies, Acute myeloid leukemia, Performance status, business.industry, Older, Treatment, Myeloid leukemia, Retrospective cohort study, medicine.disease, Clinical trial, Leukemia, Myeloid, Acute, Leukemia, Oncology, 030220 oncology & carcinogenesis, Geriatrics and Gerontology, business
Abstract

Objectives: Treatment of older patients with acute myeloid leukemia (AML) is still controversial. To facilitate treatment decisions, the “fitness criteria” proposed by Ferrara et al. (Leukemia, 2013), including age > 75 years, performance status and comorbidities, were verified retrospectively in 699 patients with AML (419 de-novo, 280 secondary AML), diagnosed at 8 Hematological Centers (REL). Methods: Patients were categorized in FIT to intensive chemotherapy (i-T) (292, 42.5%), UNFIT to i-T (289, 42.1%), or unfit even to non-intensive therapy (non i-T) (FRAIL) (105, 15.3%). Biological characteristics and treatment actually received by patients [i-T, 274 patients (39.2%); non i-T, 134 (19.2%), best-supportive care (BSC), 291 (41.6%)] were recorded. Results: “Fitness criteria” were easily applicable in 98.1% of patients. Overall concordance between “fitness criteria” and treatment actually received by patients was high (79.4%), 76% in FIT, 82.7% in UNFIT and 80% in FRAIL patients. Fitness independently predicted survival (median survival: 10.9, 4.2 and 1.8 months in FIT, UNFIT and FRAIL patients, respectively; p = 0.000), as confirmed also by multivariate analysis. In FRAIL patients, survival with any treatment was no better than with BSC, in UNFIT non i-T was as effective as i-T and better than BSC, and in FIT patients i-T was better than non i-T or BSC. In addition, a non-adverse risk AML, an ECOG PS

Published
2021

140. Evolutionary Portrait of Adult Core-Binding Factor Leukemia Patients Treated with a Continuation Therapy with Midostaurin: Preliminary Results

Author

Roberto Cairoli, Arianna Gatti, Giovanni Grillo, Monica Fumagalli, Mauro Krampera, Patrizia Zappasodi, Erika Borlenghi, Elisabetta Todisco, Marta Ubezio, Massimo Bernardi, Alfredo Molteni, Claudia Basilico, Mauro Turrini, Rosa Greco, Valentina Mancini, Marta Riva, Beatrice De Marco, Marta Rachele Stefanucci, Bruno Brando, Silvio Marco Veronese, Alessandro Beghini, Cairoli, R, Gatti, A, Grillo, G, Fumagalli, M, Krampera, M, Zappasodi, P, Borlenghi, E, Todisco, E, Ubezio, M, Bernardi, M, Molteni, A, Basilico, C, Turrini, M, Greco, R, Mancini, V, Riva, M, De Marco, B, Stefanucci, M, Brando, B, Veronese, S, and Beghini, A

Subjects
MED/15 - MALATTIE DEL SANGUE, Immunology, Cell Biology, Hematology, CBFL, Midostaurin, Biochemistry
Published
2022

141. Next-generation sequencing improves BCR-ABL1 mutation detection in Philadelphia chromosome-positive acute lymphoblastic leukaemia

Author

Fabio Stagno, Flavio Mignone, Erika Borlenghi, Elena Maino, Cristina Papayannidis, Simona Soverini, Manuela Stulle, Annalisa Imovilli, Claudia Basilico, Sabina Russo, Claudio Fozza, Chiara Sartor, Stefania Stella, Michele Cavo, Mario Annunziata, Roberta Minari, Federica Sorà, Michele Baccarani, Caterina De Benedittis, Luana Bavaro, Margherita Martelli, Francesco Albano, Massimiliano Bonifacio, Giovanni Martinelli, Elisabetta Abruzzese, Sara Galimberti, Soverini S., Martelli M., Bavaro L., De Benedittis C., Papayannidis C., Sartor C., Sora F., Albano F., Galimberti S., Abruzzese E., Annunziata M., Russo S., Stulle M., Imovilli A., Bonifacio M., Maino E., Stagno F., Maria Basilico C., Borlenghi E., Fozza C., Mignone F., Minari R., Stella S., Baccarani M., Cavo M., and Martinelli G.

Subjects
Oncology, Male, Neoplasm, Residual, bcr-abl, Drug Resistance, Fusion Proteins, bcr-abl, medicine.disease_cause, Tyrosine-kinase inhibitor, 0302 clinical medicine, hemic and lymphatic diseases, tyrosine kinase inhibitors, Medicine, Philadelphia Chromosome, Sanger sequencing, Mutation, Philadelphia Chromosome Positive, High-Throughput Nucleotide Sequencing, Hematology, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, acute lymphoblastic leukemia, BCR-ABL1, mutations, NGS, Adult, Aged, Clinical Decision-Making, Drug Resistance, Neoplasm, Female, Humans, Protein Kinase Inhibitors, Residual, 030220 oncology & carcinogenesis, symbols, medicine.medical_specialty, medicine.drug_class, DNA sequencing, 03 medical and health sciences, symbols.namesake, Internal medicine, business.industry, Fusion Proteins, Minimal residual disease, Mutation testing, Neoplasm, Lymphoblastic leukaemia, business, 030215 immunology
Abstract

BCR-ABL1 kinase domain mutation testing in tyrosine kinase inhibitor (TKI)-resistant Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) patients is routinely performed by Sanger sequencing (SS). Recently, next-generation sequencing (NGS)-based approaches have been developed that afford greater sensitivity and straightforward discrimination between compound and polyclonal mutations. We performed a study to compare the results of SS and NGS in a consecutive cohort of 171 Ph+ ALL patients. At diagnosis, 0/44 and 3/44 patients were positive for mutations by SS and NGS respectively. Out of 47 patients with haematologic resistance, 45 had mutations according to both methods, but in 25 patients NGS revealed additional mutations undetectable by SS. Out of 80 patients in complete haematologic response but with BCR-ABL1 ≥0·1%, 28 (35%) and 52 (65%) were positive by SS and NGS respectively. Moreover, in 12 patients positive by SS, NGS detected additional mutations. NGS resolved clonal complexity in 34 patients with multiple mutations at the same or different codons and identified 35 compound mutations. Our study demonstrates that, in Ph+ ALL on TKI therapy, NGS enables more accurate assessment of mutation status both in patients who fail therapy and in patients with minimal residual disease above 0·1%.

Published
2020

142. Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas.

Author

Basu-Roy, U, Seo, E, Ramanathapuram, L, Rapp, T B, Perry, J A, Orkin, S H, Mansukhani, A, and Basilico, C

Subjects
*OSTEOSARCOMA, *CANCER stem cells, *TUMORS, *SARCOMA, *CHILDHOOD cancer, *GENETIC mutation, *BIOMARKERS, *WNT genes
Abstract

Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

144. Treatment of Elderly Patients with Acute Promyelocytic Leukemia: A Real Life Experience of the 'Rete Ematologica Lombarda'

Author

Patrizia Zappasodi, Erika Ravelli, Roberto Cairoli, Monica Fumagalli, Mauro Turrini, Federico Lussana, Elisabetta Todisco, Erika Borlenghi, Massimo Bernardi, Silvia Cantoni, Valentina Mancini, Chiara Cattaneo, Nicola Stefano Fracchiolla, Livia Leuzzi, Giuseppe Rossi, Giambattista Bertani, Claudia Basilico, Mancini, V, Borlenghi, E, Leuzzi, L, Basilico, C, Bernardi, M, Zappasodi, P, Fumagalli, M, Todisco, E, Cattaneo, C, Lussana, F, Bertani, G, Ravelli, E, Fracchiolla, N, Turrini, M, Rossi, G, Cantoni, S, and Cairoli, R

Subjects
Response rate (survey), medicine.medical_specialty, education.field_of_study, Performance status, business.industry, Proportional hazards model, medicine.medical_treatment, Immunology, Population, Cell Biology, Hematology, Biochemistry, Chemotherapy regimen, Log-rank test, Internal medicine, Medicine, business, Adverse effect, education, Neoadjuvant therapy
Abstract

Background Acute promyelocytic leukemia (APL) in the elderly has a favourable outcome in a significant proportion of patients (pts). Elderly and frail pts are usually treated with attenuated treatment schedules, mostly "according to medical judgment". The combination of all-trans retinoic (ATRA) and anthracycline-based chemotherapy (CT) has been the mainstay of treatment for many years. Alternative approaches, such as arsenic trioxide (ATO) and gentuzumab ozogamicin (GO) have recently been tested with success in this setting, even though no large series of elderly pts treated with CT-free first-line treatment have been published yet. Moreover, neither a "standard of care approach" nor a specific prognostic score system have been developed to guide physician in choosing the most adequate treatment schedule in this setting. Objective Aim of the present preliminary survey was to assess genetic and clinical features of APL in pts over 60 yrs. This cut off reflects the definition of "elderly patient" in most Italian APL GIMEMA trials. Moreover, both the real life outcome and safety data after either conventional anthracycline-based CT or alternative CT-free approaches were analysed. OS, response rate to either regimens and adverse event occurrence were collected. Methods This retrospective multicenter REL (Rete Ematologica Lombarda) survey, enrolled a total of 101 consecutive APL pts aged ≥60, treated between 2000-2018. Demographics, clinical data and therapy outcome data were recorded in a dedicated patient's report form. Statistical analysis was performed using the Kaplan Maier method, Log-rank test and Cox regression. Results For analysis, pts were grouped into different categories according to age and fitness. Tables 1 and 2 summarise clinical charcteristics and treatment administered. Performance status (PS) and number of comorbidities increase with age. Twentynine of 102 (28,4%) and 9/102 (8,8%) pts had a history of or subsequently developed a solid tumor respectively. High frequency of additive cytogenetic abnormalities was observed as well. CT+ATRA was preferentially administered, mostly with attenuated intensity, to younger pts with better PS, while ATO+ATRA was preferred in pts with reduced cardiac function and ATRA monotherapy was reserved to frail or over 80 yrs old pts. Rates of differentiation syndrome or infections or cardiac events were similar in the different treatment groups. Overall, complete remission (CR) rate after induction therapy was 94.16% [CI95%: 87,5%-97,8% ]. At a median follow-up of 40 mos (range 0-199), the overall relapse rate was 24%. Median time to relapse was 7 mos in 1/8 (12,5%) ATRA monotherapy treated pts and 13 mos (range 5-66) in the 23/68 (33,8%) pts receiving CT+ATRA. No relapse occurred among the 22 pts treated with ATO+ATRA (p 0.005). OS and EFS were significantly associated with pts' age (HR 9% and 7.6%; p Conclusion This survey confirms that elderly and frail APL pts may benefit from ATO-based regimens. Reduced-dose antracycline-based CT, appears to be less effective, with high rate of relapse in elderly pts. Scoring systems and prospective data are needed in order to better define treatment strategies aiming to further improve outcome in this challenging but growing population. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria.

Published
2019

145. Fibroblast Growth Factor Signaling Uses Multiple Mechanisms To Inhibit Wnt-Induced Transcription in Osteoblasts

Author

Alka Mansukhani, Greg Holmes, Davide Ambrosetti, Claudio Basilico, Ambrosetti D, Holmes G, Mansukhani A, and Basilico C.

Subjects
Time Factors, Beta-catenin, Transcription, Genetic, Down-Regulation, Fibroblast growth factor, Cell Line, Wnt3 Protein, Mice, HMGB Proteins, Wnt3A Protein, medicine, Animals, Humans, RNA, Messenger, Molecular Biology, Transcription factor, beta Catenin, Osteoblasts, biology, SOXB1 Transcription Factors, Wnt signaling pathway, Osteoblast, Articles, Cell Biology, Cell biology, DNA-Binding Proteins, Wnt Proteins, medicine.anatomical_structure, biology.protein, Fibroblast Growth Factor 1, Signal transduction, WNT3A, Signal Transduction, Transcription Factors
Abstract

Fibroblast growth factor (FGF) and Wnt signals are both critical for proper bone development. We previously reported that the expression of activating FGF receptor mutations in osteoblasts downregulated the expression of many genes reported as targets of Wnt signaling, suggesting an antagonistic effect between Wnt signaling, which promotes osteoblast differentiation and function, and FGF signaling, which inhibits these processes. To analyze the effect of FGF on Wnt signaling in osteoblasts, we created reporter cell lines where a Wnt-responsive promoter drives luciferase expression and showed that Wnt3a-induced luciferase expression was specifically inhibited by FGF treatment. FGF specifically prevented the formation of a Wnt-induced transcriptional complex of TCF1 and -4 with beta-catenin on DNA. FGF did not significantly affect the activation of beta-catenin, although it reduced both the expression of TCF/LEF factors and their induction by Wnt. Microarray analysis using osteoblasts treated with Wnt3a and FGF alone or in combination showed that about 70% of the genes induced by Wnt3a were downregulated by combined FGF treatment. These included novel and previously identified Wnt target genes and genes involved in osteoblast differentiation. Furthermore, FGF alone could downregulate the expression of four Fzd Wnt receptor genes. Our results show that FGF antagonizes Wnt signaling by inhibiting Wnt-induced transcription and suggest that multiple mechanisms, including downregulation of TCFs and Wnt receptors, contribute to this effect.

Published
2008

146. Efficacy of Caspofungin Addition to Trimethoprim-Sulfamethoxazole Treatment for Severe Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Author

Enrico Ragone, Riccardo Utili, Cristina Basilico, Annunziata Mattei, Paolo Grossi, Emanuele Durante-Mangoni, Utili, Riccardo, DURANTE MANGONI, Emanuele, Basilico, C, Mattei, A, Ragone, E, and Grossi, P.

Subjects
Adult, Male, Beta-1, medicine.medical_specialty, Respiratory failure, Pneumocystis pneumonia, Peptides, Cyclic, Organ transplantation, Opportunistic infection, Echinocandins, Lipopeptides, chemistry.chemical_compound, Anti-Infective Agents, Caspofungin, Internal medicine, Trimethoprim, Sulfamethoxazole Drug Combination, medicine, Humans, Intensive care medicine, Antibacterial agent, Immunosuppression Therapy, Transplantation, business.industry, Pneumonia, Pneumocystis, Organ Transplantation, Middle Aged, 3-glucan, Cyst form, Immunosuppression, bacterial infections and mycoses, medicine.disease, Trimethoprim, Pneumonia, Regimen, Treatment Outcome, chemistry, Drug Therapy, Combination, Female, business, medicine.drug
Abstract

Background Pneumocystis jiroveci pneumonia may be a life-threatening opportunistic infection in immunosuppressed solid organ transplant recipients. Despite effective treatment with high-dose trimethoprim-sulfamethoxazole and steroids, morbidity is often severe and lethality remains high. New therapeutic approaches are therefore warranted. Caspofungin, a beta-1,3-glucan synthesis inhibitor, has shown activity against the cyst forms of P. jiroveci in experimental animal models. We here report our preliminary clinical experience with caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen. Methods Four solid organ transplant patients with severe hypoxemic P. jiroveci pneumonia were treated with the combination of trimethoprim-sulfametoxazole and caspofungin. In two cases, caspofungin was added as salvage treatment due to failure of trimethoprim-sulfametoxazole monotherapy. Results In these four patients, the use of caspofungin as an additional drug to the standard trimethoprim-sulfamethoxazole regimen led to a rapid improvement and a complete cure of pneumonia. No side effects or drug interactions were observed. Discussion This preliminary clinical experience suggests that the addition of caspofungin to trimethoprim-sulfamethoxazole, which is active against trophic forms, may provide a synergistic activity against P. jiroveci by fully inhibiting the organism life cycle.

Published
2007

147. An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice

Author

Silvia Cavassa, Luigi Naldini, Paolo M. Comoglio, Cristina Basilico, Massimiliano Mazzone, Selma Pennacchietti, Mauro Risio, Paolo Michieli, Mazzone, M., Basilico, C., Cavassa, S., Pennacchietti, S., Risio, M., Naldini, Luigi, Comoglio, P. M., and Michieli, P.

Subjects
Glutamine, Cell, lentiviral vectors, urokinase, Protein Engineering, Extracellular matrix, Mice, gene-transfer, Methionine, c-met receptor, 0302 clinical medicine, Transduction, Genetic, Neoplasms, serine-protease, Neoplasm Metastasis, Receptor, 0303 health sciences, Hepatocyte Growth Factor, beta-chain, General Medicine, Protein-Tyrosine Kinases, Recombinant Proteins, Extracellular Matrix, Tumor Burden, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Hepatocyte growth factor, Collagen, factor/scatter factor, invasive growth, Tyrosine kinase, medicine.drug, Proteases, purification, Genetic Vectors, Transplantation, Heterologous, Mice, Nude, Mitosis, Breast Neoplasms, Biology, Article, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, 030304 developmental biology, Carcinoma, Lentivirus, Genetic Therapy, Enzyme Activation, Transplantation, Amino Acid Substitution, Tumor progression, proteolytic activation, Cancer research, Neoplasm Transplantation
Abstract

Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions. ispartof: Journal of clinical investigation vol:114 issue:10 pages:1418-1432 ispartof: location:United States status: published

Published
2004

148. Targeting the tumor and its microenvironment by a dual-function decoy Met receptor

Author

Silvia Cavassa, Cristina Basilico, Paolo M. Comoglio, Massimiliano Mazzone, Antonino Sottile, Paolo Michieli, Luigi Naldini, Michieli, P., Mazzone, M., Basilico, C., Cavassa, S., Sottile, A., Naldini, Luigi, and Comoglio, P. M.

Subjects
Cancer Research, Lung Neoplasms, hepatocellular carcinomas, lentiviral vectors, Angiogenesis Inhibitors, chemistry.chemical_compound, Mice, 0302 clinical medicine, Tumor Cells, Cultured, Receptor, 0303 health sciences, Neovascularization, Pathologic, Hepatocyte Growth Factor, Gene Transfer Techniques, tyrosine kinase, hepatocyte growth-factor, Proto-Oncogene Proteins c-met, scatter-factor, 3. Good health, Angiogenesis inhibitor, Oncology, 030220 oncology & carcinogenesis, Hepatocyte growth factor, Female, factor/scatter factor, invasive growth, Decoy, Tyrosine kinase, Dimerization, medicine.drug, C-Met, Genetic Vectors, Mice, Nude, Biology, Disease-Free Survival, Viral vector, 03 medical and health sciences, In vivo, medicine, Animals, Humans, Neoplasm Invasiveness, 030304 developmental biology, Lentivirus, Mammary Neoplasms, Experimental, Cell Biology, Genetic Therapy, Molecular biology, Xenograft Model Antitumor Assays, angiogenesis inhibitor, chemistry, Cancer research, somatic mutations, c-met
Abstract

Met, the receptor for hepatocyte growth factor (HGF), is activated in human cancer by both ligand-dependent and -independent mechanisms. We engineered a soluble Met receptor (decoy Met) that interferes with both HGF binding to Met and Met homodimerization. By lentiviral vector technology, we achieved local or systemic delivery of decoy Met in mice. We provide evidence that in vivo expression of decoy Met (1) inhibits tumor cell proliferation and survival in a variety of human xenografts, (2) impairs tumor angiogenesis by preventing host vessel arborization, (3) suppresses or prevents the formation of spontaneous metastases, and (4) synergizes with radiotherapy in inducing tumor regression, without (5) affecting housekeeping physiological functions in the adult animal. ispartof: Cancer cell vol:6 issue:1 pages:61-73 ispartof: location:United States status: published

Published
2004

149. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1 infected individuals with virological failure to all three antiretroviral-drug classes

Author

Ledergerber, B, Lundgren, Jd, Walker, As, Sabin, C, Justice, A, Reiss, P, Mussini, C, Wit, F, d'Arminio Monforte, A, Weber, R, Fusco, G, Staszewski, S, Law, M, Hogg, R, Lampe, F, Gill, Mj, Castelli, Francesco, Phillips, An, Rooney, P. q, Taylor, S. q, Couldwell, D. r, Austin, D. s, Block, M. s, Clemons, J. s, Finlayson, R. s, Petoumenos, K. s, Quan, D. s, Smith, D. s, O'Connor, C. t, Gorton, C. t, Allen, D. u, Mulhall, B. u, Mutimer, K. v, Keeffe, N. v, Cooper, D. w, Carr, A. w, Miller, J. w, Pell, C. w, Ellis, D. x, Baker, D. y, Kidd, J. y, Mcfarlane, R. y, Liang, M. T. z, Brown, Aa, K., Huffam, Ab, S., Savage, Ab, J., Morgan, Knibbs, Ab, P., Sowden, Ac, D., Walker, Ac, A., Orth, Ad, D., Lister, Ad, G., Chuah, Ae, J., Fankhauser, Ae, W., Dickson, Ae, B., Bradford, Af, D., Wilson, Af, C., Ree, Ag, H., Magon, Anderson, Ah, J., Moore, Ah, R., Russell, Ah, D., Mcgovern, Ah, G., Mcnair, Bal, Fairley, Ah, K., Roth, Ai, N., Ai, B., Strecker, Ai, S., Ai, D., Wood, Ai, H., Mijch, Aj, A., Hoy, Aj, J., Pierce, Mccormack, Aj, C., Watson, Aj, K., Medland, Ak, N., Daye, Al, J., Mallal, Am, S., French, Am, M., Skett, Am, J., Maxwel, Am, D., Cain, Am, A., Montroni, An, M., Scalise, An, G., Costantini, An, A., Giacometti, Tirelli, Ao, U., Nasti, Ao, G., Pastore, Ap, G., Ladisa, Ap, N., Perulli, M. L., Ap, Suter, Aq, F., Arici, Aq, C., Maggiolo, Chiodo, Ar, F., Gritti, F. M., Ar, Colangeli, Ar, V., Fiorini, Ar, C., Guerra, Ar, L., Carosi, As, G., Cadeo, G. P., As, Minardi, As, C., Vangi, As, D., Paraninfo, Casari, As, S., Pan, As, A., Patroni, Torti, Quiros, Roldan, As, E., Tomasoni, As, L., Moretti, As, F., Nasta, As, P., Uccelli, M. C., As, Bertelli, Rizzardini, At, G., Migliorino, At, M., Abeli, At, C., Manconi, P. E., Au, Piano, Au, P., Ferraro, Av, T., Scerbo, Av, A., Pizzigallo, Aw, E., Ricci, Aw, F., Santoro, Ax, D., Pusterla, Ax, L., Carnevale, Ay, G., Galloni, Ay, D., Viganò, Az, P., Mena, Az, M., Ghinelli, Ba, F., Sighinolfi, Ba, L., Leoncini, Bb, F., Mazzotta, Pozzi, Bb, M., Caputo, Lo, Bb, S., Angarano, Bc, G., Grisorio, Bc, B., Ferrara, Bc, S., Grima, Bd, P., Tundo, Pagano, Be, G., Piersantelli, Be, N., Alessandrini, Be, A., Piscopo, Be, R., Toti, Bf, M., Chigiotti, Bf, S., Soscia, Bg, F., Tacconi, Bg, L., Orani, Bh, A., Perini, Bh, P., Nigro, Bh, M., Scasso, Bi, A., Vincenti, Scalzini, Bj, A., Fibbia, Bj, G., Moroni, Bk, M., Lazzarin, Bk, A., Cargnel, Vigevani, G. M., Bk, Caggese, Bk, L., Tordato, Bk, F., Novati, Bk, R., Galli, Merli, Bk, S., Pastecchia, Bk, C., Moioli, Esposito, Bl, R., Abrescia, Bm, N., Chirianni, Bm, A., Izzo, Bm, C., Piazza, Bm, M., Marco, De, Montesarchio, Bm, V., Manzillo, Bm, E., Nappa, Bm, S., Colomba, Bn, A., Abbadessa, Bn, V., Prestileo, Bn, T., Mancuso, Bn, S., Ferrari, Bo, C., Pzzaferri, Bo, P., Filice, Bp, G., Minoli, Bp, L., Bruno, Bp, R., Maserati, Bp, S., Tinelli, Bp, C., Pauluzzi, Bq, S., Baldelli, Bq, F., Petrelli, Br, E., Cioppi, Br, A., Alberici, Bs, F., Ruggieri, Bs, A., Menichetti, Bt, F., Martinelli, Bt, C., Stefano, De, Bu, C., Gala, La, Bu, A., Zauli, Bv, T., Ballardini, Bv, G., Magnani, Bw, G., Ursitti, M. A., Bw, Arlotti, Bx, M., Ortolani, Bx, P., Ortona, By, L., Dianzani, By, F., Ippolito, By, G., Antinori, Bz, A., Antonucci, Bz, G., D'Elia, Bz, S., Narciso, Bz, P., Petrosillo, Bz, N., Vullo, Bz, V., Luca, De, Del, Forno, Bz, L., Zaccarelli, Bz, M., Longis, De, Ciardi, D'Offizi, Noto, Lichtner, Capobianchi, M. R., Bz, Girardi, Bz, E., Pezzotti, Rezza, Mura, M. S., Ca, Mannazzu, Ca, M., Caramello, Cb, P., Sinicco, Cb, A., Soranzo, M. L., Cb, Gennero, Cb, L., Sciandra, Cb, M., Salassa, Cb, B., Grossi, P. A., Cc, Basilico, Cc, C., Poggio, Cd, A., Bottari, Cd, G., Raise, Ce, E., Pasquinucci, Ce, S., Lalla, De, Cf, F., Tositti, Cf, G., Resta, Cg, F., Chimienti, Cg, A., Lepri, Cozzi, Ch, A., Bachmann, Fb, S., Battegay, Fb, M., Bernasconi, Fb, E., Bucher, Fb, H., Bürgisser, Fb, P., Cattacin, Egger, Erb, Fierz, Fb, W., Fischer, Flepp, Fontana, Fb, A., Francioli, Furrer, H. J., Fb, Gorgievski, Günthard, Hirschel, Fb, B., Kaiser, Fb, L., Kind, Fb, C., Klimkait, Fb, T., Lauper, Fb, U., Opravil, Paccaud, Fb, F., Pantaleo, Fb, G., Perrin, Piffaretti, J. C., Fb, Rickenbach, Rudin, Schüpbach, Fb, J., Speck, Fb, R., Tarr, Telenti, Trkola, Vernazza, Yerly, Wolf, De, Ci, F., Van, Sighem, A. I., Ci, Van, Valkengoed, Ci, I., Gras, Ci, L., Bronsveld, Ci, W., Veldkamp, Ci, A., Prins, J. M., Cj, Bos, J. C., Cj, Schattenkerk, Eeftinck, J. K. M., Cj, Godfried, M. H., Cj, Lange, J. M. A., Cj, Lowe, S. H., Cj, van der Meer, J. T. M., Cj, Nellen, F. J. B., Cj, Pogany, Cj, K., van der Poll, Cj, T., Ruys, T. A., Cj, Sankatsing, Cj, S., van der Valk, Cj, M., Van, Vonderen, M. G. A., Cj, Wit, F. W. M. N., Cj, Van, Eeden, Cj, A., Ten, Veen, J. H., Cj, Van, Dam, P. S., Cj, Hillebrand, Haverkort, M. E., Cj, Brinkman, Frissen, P. H. J., Cj, Weigel, H. M., Cj, Mulder, J. W., Cj, Van, Gorp, E. C. M., Cj, Meenhorst, P. L., Cj, Mairuhu, A. T. A., Cj, Veenstra, Cj, J., Danner, S. A., Cj, Van, Agtmael, M. A., Cj, Claessen, F. A. P., Cj, Geerlings, S. E., Cj, Perenboom, R. M., Cj, Jurriaans, Back, N. K. T., Cj, Cuijpers, Rietra, P. J. G. M., Cj, Roozendaal, K. J., Cj, Pauw, Cj, W., Van, Zanten, A. P., Cj, Smits, P. H. M., Cj, Von, Blomberg, B. M. E., Cj, Savelkoul, Cj, P., Zaaijer, Cj, H., Beijnen, Crommentuyn, K. M. L., Cj, Huitema, A. D. R., Cj, Kappelhoff, Cj, B., Maat, De, M. M. R., Cj, Richter, Ck, C., van der Berg, Ck, J., Van, Leusen, Ck, R., Swanink, Vriesendorp, Cl, R., Jeurissen, F. J. F., Cl, Kauffmann, R. H., Cm, Koger, E. L. W., Cm, Franck, P. F. H., Cm, Lampe, A. S., Cm, Jansen, C. L., Cm, Bravenboer, Cn, B., Ten, Napel, C. H. H., Co, Mudrikova, Co, T., Hendriks, Co, R., Sprenger, H. G., Cp, Miesen, W. M. A. J., Cp, Schirm, Cp, J., Benne, Cp, D., Ten, Kate, R. W., Cq, Veenendaal, Cq, D., Van, Houte, D. P. F., Cr, Leemhuis, M. P., Cr, Pole, Cr, M., Storm, Cr, H., Van, Zeijl, J. H., Cr, Kroon, F. P., Cs, Schippers, E. F., Cs, Kroes, A. C. M., Cs, Claas, H. C. J., Cs, Schreij, Ct, G., van de Geest, Ct, S., Verbon, Ct, A., Bruggeman, C. A. M. V. A., Ct, Goossens, V. J., Ct, Koopmans, P. P., Cu, Telgt, Cu, M., van der Ven, A. J. A. M., Cu, Burger, D. M., Cu, Hugen, P. W. H., Cu, Galama, J. M. D., Cu, Poort, Y. A. G. M., Cu, van der Ende, M. E., Cv, Gyssens, I. C., Cv, Marie, De, Cv, S., Nouwen, J. L., Cv, Niesters, M. G., Cv, Osterhaus, A. D. M. E., Cv, Schutten, Cv, M., Juttmann, J. R., Cw, Buiting, A. G. M., Cw, Swaans, C. A. M., Cw, Schneider, M. M. E., Cx, Bonten, M. J. M., Cx, Borleffs, J. C. C., Cx, Hoepelman, I. M., Cx, Jaspers, C. A. J. J., Cx, Schouten, Cx, I., Schurink, C. A. M., Cx, Boucher, C. A. B., Cx, Schuurman, Cx, R., Blok, W. L., Cy, Groeneveld, P. H. P., Cz, Boel, Da, E., Jansz, A. F., Da, Dabis, Db, F., Thiebaut, Db, R., Chêne, Db, G., Lawson, Ayayi, Db, S., Meyer, Dc, L., Boufassa, Dc, F., Hamouda, Dd, O., De, P., De, G., Touloumi, Df, G., Hatzakis, Df, A., Karafoulidou, Katsarou, Df, O., Brettle, Dg, R., Del, Amo, Dh, J., Del, Romero, Van, Asten, Di, L., Van, Benthem, Di, B., Di, M., Coutinho, Di, R., Kirk, Dj, O., Pedersen, Dj, C., Hernández, Aguado, Dk, I., Pérez, Hoyos, Dk, S., Eskild, Dl, A., Bruun, J. N., Dl, Sannes, Dl, M., Lee, Dm, C., Johnson, A. M., Dn, Babiker, Dn, A., Darbyshire, Dn, J., Gill, Dn, N., Porter, Dn, K., Do, P., Vanhems, Do, M., Cooper, Dp, D., Kaldor, Dpdq, J., Ashton, Dp, L., Dq, D., Dq, L., Vizzard, Dq, J., Muga, Dr, R., Ds, P., Dt, J., Cayla, Du, J., Garcia de Olalla, Du, P., Day, N. E., Dv, Angelis, De, Dv, D., Fb, K., Dw, A., Dw, S., Dw, J., Tyrer, Dw, F., Beral, Fb, V., Fb, N., Raffanti, Becker, Scarsella, Braun, Most, Balu, Gilbert, Fleenor, Ising, Dieterich, Fb, D., Fusco, Losso, Dx, M., Duran, Dx, A., Vetter, Dy, N., Clumeck, Dz, N., Wit, De, Dz, S., Kabeya, Dz, K., Poll, Dz, B., Colebunders, Dz, R., Machala, Ea, L., Rozsypal, Ea, H., Nielsen, Eb, J., Lundgren, Eb, O., Olsen, C. H., Eb, Gerstoft, Katzenstein, Eb, T., Hansen, A. B. E., Eb, Skinhøj, Eb, P., Eb, C., Zilmer, Ec, K., Rauka, Ec, M., Katlama, Ed, C., De, Sa, Ed, M., Viard, J. P., Ed, Saint, Marc, Ed, T., Ed, P., Pradier, Dietrich, Ee, M., Manegold, Ee, C., Van, Lunzen, Ee, J., Stellbrink, H. J., Ee, Miller, Ee, V., Goebel, F. D., Ee, Salzberger, Ee, B., Rockstroh, Kosmidis, Ef, J., Gargalianos, Ef, P., Sambatakou, Ef, H., Perdios, Panos, Ef, G., Filandras, Ef, A., Banhegyi, Eg, D., Mulcahy, Eh, F., Yust, Ei, I., Burke, Ei, M., Pollack, Ei, S., Hassoun, Ei, J., Sthoeger, Ei, Z., Maayan, Vella, Ej, S., Chiesi, Ej, A., Ej, C., Pristerá, Ej, R., Ej, F., Gabbuti, Bedini, Ej, E., Ej, V., Santopadre, Ej, P., Franci, Ej, M., Castagna, Viksna, Ek, L., Rozentale, Ek, B., Chaplinskas, El, S., Hemmer, Em, R., Staub, Em, T., En, J., Maeland, En, A., Ormaasen, En, V., Knysz, Eo, B., Gasiorowski, Eo, J., Horban, Eo, A., Prokopowicz, Eo, D., Wiercinska, Drapalo, Boron, Kaczmarska, Pynka, Eo, M., Beniowski, Trocha, Eo, H., Smiatacz, Eo, T., Antunes, Ep, F., Mansinho, Ep, K., Maltez, Duiculescu, Eq, D., Streinu, Cercel, Eq, A., Mokrás, Er, M., Staneková, Er, D., González, Lahoz, Es, J., Diaz, Es, B., García, Benayas, Es, T., Martin, Carbonero, Es, L., Soriano, Es, V., Clotet, Jou, Es, A., Conejero, Tural, Es, C., Gatell, J. M., Es, Miró, Zamora, Blaxhult, Et, A., Karlsson, Pehrson, Et, P., Eu, P., Eu, B., Schiffer, Eu, V., Eu, H., Chentsova, Ev, N., Barton, Ew, S., A. M., Ew, Mercey, Ew, D., Phillips, Ew, A., Youle, Ew, M., M. A., Ew, Mocroft, Murphy, Weber, Ew, J., Scullard, Ew, G., Fisher, Ew, R., Loveday, Ew, C., Ex, B., Ruiz, Ex, L., Helm, E. B., Fb, Carlebach, Mösch, Müller, Haberl, Korn, Stephan, Bickel, Gute, Locher, Lutz, Klauke, Doerr, H. W., Fb, Stürmer, Dauer, Jennings, Alexander, Braitstein, Chan, Cote, Gataric, Harrigan, P. R., Fb, Harris, Bonner, Montaner, O'Shaughnessy, Yip, Chaloner, Gumley, Ransom, Sabin, C. A., Fb, Lipman, Ey, J., Read, Ey, R., Ez, F., Riccio, Fa, G., Borghi, AII - Amsterdam institute for Infection and Immunity, APH - Amsterdam Public Health, Infectious diseases, Global Health, Other departments, Public and occupational health, General Internal Medicine, Center of Experimental and Molecular Medicine, Ledergerber, B, Lundgren, Jd, Walker, A, Sabin, C, Justice, A, Reiss, P, Mussini, C, Wit, F, Monforte, Ad, Weber, R, Fusco, G, Staszewski, S, Law, M, Hogg, R, Lampe, F, Gill, Mj, Castelli, F, Phillips, An, Fusco, Gp, Rooney, P, Taylor, S, Couldwell, D, Austin, D, Block, M, Clemons, J, Finlayson, R, Petoumenos, K, Quan, D, Smith, D, O'Connor, C, Gorton, C, Allen, D, Mulhall, B, Mutimer, K, Keeffe, N, Cooper, D, Carr, A, Miller, J, Pell, C, Ellis, D, Baker, D, Kidd, J, Mcfarlane, R, Liang, Mt, Brown, K, Huffam, S, Savage, J, Morgan, S, Knibbs, P, Sowden, D, Orth, D, Lister, G, Chuah, J, Fankhauser, W, Dickson, B, Bradford, D, Wilson, C, Ree, H, Magon, H, Anderson, J, Moore, R, Russell, D, Mcgovern, G, Mcnair, R, Bal, J, Fairley, K, Roth, N, Eu, B, Strecker, S, Wood, H, Mijch, A, Hoy, J, Pierce, A, Mccormack, C, Watson, K, Medland, N, Daye, J, Mallal, S, French, M, Skett, J, Maxwel, D, Cain, A, Montroni, M, Scalise, G, Costantini, A, Giacometti, A, Tirelli, U, Nasti, G, Pastore, G, Ladisa, N, Perulli, Ml, Suter, F, Arici, C, Chiodo, F, Gritti, Fm, Colangeli, V, Fiorini, C, Guerra, L, Carosi, G, Cadeo, Gp, Minardi, C, Vangi, D, Rizzardini, G, Migliorino, G, Manconi, Pe, Piano, P, Ferraro, T, Scerbo, A, Pizzigallo, E, Ricci, F, Santoro, D, Pusterla, L, Carnevale, G, Galloni, D, Vigano, P, Mena, M, Ghinelli, F, Sighinolfi, L, Leoncini, F, Mazzotta, F, Pozzi, M, Lo Caputo, S, Angarano, G, Grisorio, B, Ferrara, S, Grima, P, Tundo, P, Pagano, G, Piersantelli, N, Alessandrini, A, Piscopo, R, Toti, M, Chigiotti, S, Soscia, F, Taccooni, L, Orani, A, Perini, P, Scasso, A, Vincenti, A, Scalzini, A, Fibbia, G, Moroni, M, Lazzarin, A, Cargnel, A, Vigevani, Gm, Caggese, L, Tordato, F, Novati, R, Galli, A, Merli, S, Pastecchia, C, Moioli, C, Esposito, R, Abrescia, N, Chirianni, A, Izzo, C, Piazza, M, De Marco, M, Montesarchio, V, Manzillo, E, Nappa, S, Colomba, A, Abbadessa, V, Prestileo, T, Mancuso, S, Ferrari, C, Pzzaferri, P, Filice, G, Minoli, L, Bruno, R, Maserati, R, Pauluzzi, S, Baldelli, F, Petrelli, E, Cioppi, A, Alberici, F, Ruggieri, A, Menichetti, F, Martinelli, C, De Stefano, C, La Gala, A, Zauli, T, Ballardini, G, Magnani, G, Ursitti, Ma, Arlotti, M, Ortolani, P, Ortona, L, Dianzani, F, Ippolito, G, Antinori, A, Antonucci, G, D'Elia, S, Narciso, P, Petrosillo, N, Vullo, V, De Luca, A, Del Forno, L, Zaccarelli, M, De Longis, P, Ciardi, M, D'Offizi, G, Noto, P, Lichtner, M, Capobianchi, Mr, Girardi, E, Pezzotti, P, Rezza, G, Mura, M, Mannazzu, M, Caramello, P, Sinicco, A, Soranzo, Ml, Gennero, L, Sciandra, M, Salassa, B, Grossi, Pa, Basilico, C, Poggio, A, Bottari, G, Raise, E, Pasquinucci, S, De Lalla, F, Tositti, G, Resta, F, Chimienti, A, Lepri, Ac, Bachmann, S, Battegay, M, Bernasconi, E, Bucher, H, Burgisser, P, Cattacin, S, Egger, M, Erb, P, Fierz, W, Fischer, M, Flepp, M, Fontana, A, Francioli, P, Furrer, Hj, Gorgievski, M, Hirschel, B, Kaiser, L, Kind, C, Klimkait, T, Lauper, U, Opravil, M, Paccaud, F, Pantaleo, G, Perrin, L, Piffaretti, Jc, Rickenbach, M, Rudin, C, Schupbach, J, Speck, R, Tarr, P, Telenti, A, Trkola, A, Vernazza, P, Yerly, S, de Wolf, F, van Sighem, Ai, van Valkengoed, I, Gras, L, Bronsveld, W, Prins, Jm, Bos, Jc, Schattenkerk, Jkme, Godfried, Mh, Lange, Jma, Lowe, Sh, van der Meer, Jtm, Nellen, Fjb, Pogany, K, van der Poll, T, Ruys, Ta, Sankatsing, S, van der Valk, M, van Vonderen, Mga, Wit, Fwmn, van Eeden, A, ten Veen, Jh, van Dam, P, Hillebrand Haverkort, Me, Brinkman, K, Frissen, Phj, Weigel, Hm, Mulder, Jw, van Gorp, Ecm, Meenhorst, Pl, Mairuhu, Ata, Veenstra, J, Danner, Sa, Van Agtmael, Ma, Claessen, Fap, Geerlings, Se, Perenboom, Rm, Richter, C, van der Berg, J, van Leusen, R, Vriesendorp, R, Jeurissen, Fjf, Kauffmann, Rh, Koger, Elw, Bravenboer, B, ten Napel, Chh, Mudrikova, T, Sprenger, Hg, Miesen, Wmaj, ten Kate, Rw, van Houte, Dpf, Leemhuis, Mp, Pole, M, Kroon, Fp, Schippers, Ef, Schreij, G, van de Geest, S, Verbon, A, Koopmans, Pp, Telgt, M, van der Ven, Ajam, van der Ende, Me, Gyssens, Ic, de Marie, S, Nouwen, Jl, Juttmann, Jr, Schneider, Mme, Bonten, Mjm, Borleffs, Jcc, Hoepelman, Im, Jaspers, Cajj, Schouten, I, Schurink, Cam, Blok, Wl, Groenveld, Php, Jurriaans, S, Back, Nkt, Cuijpers, T, Rietra, Pjgm, Roozendaal, Kj, Pauw, W, van Zanten, Ap, Smits, Phm, von Blomberg, Bme, Savelkoul, P, Zaaijer, H, Swanink, C, Franck, Pfh, Lampe, A, Jansen, Cl, Hendriks, R, Schirm, J, Benne, D, Veenendaal, D, Storm, H, van Zeijl, Jh, Kroes, Acm, Claas, Hcj, Bruggeman, Camva, Goossens, Vj, Galama, Jmd, Poort, Yagm, Niesters, Mg, Osterhaus, Adme, Schutten, M, Buiting, Agm, Swaans, Cam, Boucher, Cab, Schuurman, R, Boel, E, Jansz, Af, Veldkamp, A, Beijnen, Jh, Crommentuyn, Kml, Huitema, Adr, Kappelhoff, B, de Maat, Mmr, Burger, Dm, Hugen, Pwh, Dabis, F, Thiebaut, R, Chene, G, Lawson Ayayi, S, Meyer, L, Boufassa, F, Hamouda, O, Touloumi, G, Hatzakis, A, Karafoulidou, A, Katsarou, O, Brettle, R, Del Amo, J, del Romero, J, van Asten, L, van Benthem, B, Prins, M, Coutinho, R, Kirk, O, Pedersen, C, Aguado, Ih, Perez Hoyos, S, Eskild, A, Bruun, Jn, Sannes, M, Lee, C, Johnson, Am, Babiker, A, Darbyshire, J, Gill, N, Porter, K, Vanhems, P, Kaldor, J, Ashton, L, Vizzard, J, Muga, R, Gill, J, Cayla, J, de Olalla, Pg, Day, Ne, De Angelis, D, Walker, S, Tyrer, F, Beral, V, Raffanti, S, Becker, S, Scarsella, A, Braun, J, Most, B, Balu, R, Gilbert, L, Fleenor, R, Ising, T, Dieterich, D, Fusco, J, Losso, M, Duran, A, Vetter, N, Clumeck, N, De Wit, S, Kabeya, K, Poll, B, Colebunders, R, Machala, L, Rozsypal, H, Nielsen, J, Lundgren, J, Olsen, Ch, Gerstoft, J, Katzenstein, T, Hansen, Abe, Skinhoj, P, Zilmer, K, Rauka, M, Katlama, C, De Sa, M, Viard, Jp, Saint Marc, T, Pradier, C, Dietrich, M, Manegold, C, van Lunzen, J, Stellbrink, Hj, Miller, V, Goebel, Fd, Salzberger, B, Rockstroh, J, Kosmidis, J, Gargalianos, P, Sambatakou, H, Perdios, J, Panos, G, Filandras, A, Banhegyi, D, Mulcahy, F, Yust, I, Burke, M, Pollack, S, Hassoun, J, Sthoeger, Z, Maayan, S, Vella, S, Chiesi, A, Pristera, R, Gabbuti, A, Bedini, A, Montesarchio, E, Santopadre, P, Franci, P, Castagna, Antonella, Viksna, L, Rozentale, B, Chaplinskas, S, Hemmer, R, Staub, T, Bruun, J, Maeland, A, Ormaasen, V, Knysz, B, Gasiorowski, J, Horban, A, Prokopowicz, D, Wiercinska Drapalo, A, Boron Kaczmarska, A, Pynka, M, Beniowski, M, Trocha, H, Smiatacz, T, Antunes, F, Mansinho, K, Maltez, F, Duiculescu, D, Streinu Cercel, A, Mokras, M, Stanekova, D, Gonzalez Lahoz, J, Diaz, B, Garcia Benayas, T, Martin Carbonero, L, Soriano, V, Clotet, B, Jou, A, Conejero, J, Tural, C, Gatell, Jm, Miro, Jm, Zamora, L, Blaxhult, A, Karlsson, A, Pehrson, P, Schiffer, V, Furrer, H, Chentsova, N, Barton, S, Mercey, D, Phillips, A, Youle, M, Johnson, Ma, Mocroft, A, Murphy, M, Weber, J, Scullard, G, Fisher, M, Loveday, C, Ruiz, L, Helm, Eb, Carlebach, A, Mosch, M, Muller, A, Haberl, A, Korn, S, Stephan, C, Bickel, M, Gute, P, Locher, L, Lutz, T, Klauke, S, Doerr, Hw, Sturmer, M, Dauer, B, Jennings, B, Alexander, C, Braitstein, P, Chan, K, Cote, H, Gataric, N, Harrigan, Pr, Harris, M, Bonner, S, Montaner, J, O'Shaughnessy, M, Wood, E, Yip, B, Chaloner, C, Gumley, H, Ransom, D, Sabin, Ca, Lipman, M, Johnson, M, Read, R, Paraninfo, G, Casari, S, Pan, A, Patroni, A, Torti, C, Quiros Roldan, E, Tomasoni, L, Moretti, F, Nasta, P, Uccelli, Mc, Bertelli, D, Nigro, M, Migliorino, M, Abeli, C, Maggiolo, F, Novati, S, Tinelli, C, Riccio, G, Borghi, V, and Esposito, R.

Subjects
Male, HAART, Human immunodeficiency virus (HIV), CD4 cell count, HIV Infections, CLINICAL PROGRESSION, medicine.disease_cause, THERAPY, HAART REGIMEN, Cohort Studies, Risk Factors, Adult, Anti-Retroviral Agents, CD4 Lymphocyte Count, Cohort Studies, Female, Follow-Up Studies, HIV Infections, HIV Protease Inhibitors, HIV-1, Humans, Male, Middle Aged, Proportional Hazards Models, Reverse Transcriptase Inhibitors, Risk Factors, Treatment Failure, Viral Load, Medicine, Treatment Failure, Mortality rate, Medicine (all), INHIBITOR, General Medicine, Middle Aged, HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1), BLIND CONTROLLED-TRIAL, medicine.anatomical_structure, Anti-Retroviral Agents, Cohort, HUMAN-IMMUNODEFICIENCY-VIRUS, Reverse Transcriptase Inhibitors, Female, Off Treatment, Viral load, Cohort study, Adult, medicine.medical_specialty, Settore MED/17 - Malattie Infettive, T cell, Internal medicine, Humans, COHORT, Proportional Hazards Models, business.industry, Proportional hazards model, DISEASE PROGRESSION, HIV Protease Inhibitors, HIV-INFECTED INDIVIDUALS, CD4 Lymphocyte Count, VIRAL LOAD, Immunology, HIV-1, business, Follow-Up Studies
Abstract

Background Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure.Methods We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months). Regression analyses were used to quantify the associations between CD4-cell-count slope, HIV-1 RNA concentration, treatment information, and demographic characteristics. Predictors of death were analysed by Cox's proportional-hazards models.Findings 2488 patients were included. 2118 (85%) had started antiretroviral therapy with single or dual therapy. During 5015 person-years of follow-up, 276 patients died (mortality rate 5.5 per 100 person-years; 3-year mortality risk 15.3% (95% Cl 13.5-17.3). Risk of death was strongly influenced by the latest CD4-cell count with a relative hazard of 15.8 (95% CI 9.28-27.0) for counts below 50 cells per muL versus above 200 cells per muL. The latest viral load did not independently predict death. For any given viral load, patients on treatment had more favourable CD4-cell-count slopes than those off treatment. For patients on treatment and with stable viral load, CD4-cell counts tended to be increasing at times when the current viral load was below 10 000 copies per mL or 1.5 log(10) copies per mL below off-treatment values.Interpretation In patients for whom viral-load suppression to below the level of detection is not possible, achievement and maintenance of a CD4-cell count above 200 per muL becomes the primary aim. Treatment regimens that maintain the viral load below 10 000 copies per mL or at least provide 1.5 log(10) copies per mL suppression below the off-treatment value do not seem to be associated with appreciable CD4-cell-count decline.

Published
2004

Catalog

Books, media, physical & digital resources
See catalog results