47 results on '"Elisa Gobbini"'
Search Results
2. Immunotherapy in NSCLC Patients With Brain and Leptomeningeal Metastases
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Thomas Pierret, Niccolò Giaj-Levra, Anne-Claire Toffart, Filippo Alongi, Denis Moro-Sibilot, and Elisa Gobbini
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lung cancer ,immunotherapy ,brain ,leptomeningeal ,metastases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Immunotherapy has now been integrated as a treatment strategy for most patients with non-small cell lung cancer (NSCLC). However, the pivotal clinical trials that demonstrated its impressive efficacy often did not include patients with active, untreated brain metastases or leptomeningeal carcinomatosis. Nevertheless, NSCLC is the most common tumor to metastasize to the brain, and patients develop brain and meningeal involvement in approximately 40 and 10% of cases, respectively. Consequently, the appropriate care of these patients is a recurrent clinical concern. Although there are many aspects that would merit further investigation to explain the mechanism of intracranial response to immune checkpoint inhibitors (ICPs), some data suggest that they are able to cross the blood–brain barrier, resulting in local tumor microenvironment modification. This results in a similar clinical benefit in patients with stable, previously treated brain metastases compared to the general population. Despite important limitations, some real-life studies have described that the ICPs’ efficacy was maintained also in less selected patients with untreated or symptomatic brain metastases. In contrast, few data are available about patients with leptomeningeal carcinomatosis. Nevertheless, neurological complications due to ICP treatment in patients with brain metastases have to be evaluated and carefully monitored. Despite the fact that limited data are available in the literature, the purpose of this review is to show that the multimodal treatment of these patients with brain metastases and/or leptomeningeal disease should be discussed during tracing of the history of the disease, participating in the local and possibly systemic control of NSCLC.
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- 2022
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3. Sae2 and Rif2 regulate MRX endonuclease activity at DNA double-strand breaks in opposite manners
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Antonio Marsella, Elisa Gobbini, Corinne Cassani, Renata Tisi, Elda Cannavo, Giordano Reginato, Petr Cejka, and Maria Pia Longhese
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checkpoint ,double-strand breaks ,MRX ,Mre11-Rad50 ,Rad53 ,Rif2 ,Biology (General) ,QH301-705.5 - Abstract
Summary: The Mre11-Rad50-Xrs2 (MRX) complex detects and processes DNA double-strand breaks (DSBs). Its DNA binding and processing activities are regulated by transitions between an ATP-bound state and a post-hydrolysis cutting state that is nucleolytically active. Mre11 endonuclease activity is stimulated by Sae2, whose lack increases MRX persistence at DSBs and checkpoint activation. Here we show that the Rif2 protein inhibits Mre11 endonuclease activity and is responsible for the increased MRX retention at DSBs in sae2Δ cells. We identify a Rad50 residue that is important for Rad50-Rif2 interaction and Rif2 inhibition of Mre11 nuclease. This residue is located near a Rad50 surface that binds Sae2 and is important in stabilizing the Mre11-Rad50 (MR) interaction in the cutting state. We propose that Sae2 stimulates Mre11 endonuclease activity by stabilizing a post-hydrolysis MR conformation that is competent for DNA cleavage, whereas Rif2 antagonizes this Sae2 function and stabilizes an endonuclease inactive MR conformation.
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- 2021
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4. The 9-1-1 Complex Controls Mre11 Nuclease and Checkpoint Activation during Short-Range Resection of DNA Double-Strand Breaks
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Elisa Gobbini, Erika Casari, Chiara Vittoria Colombo, Diego Bonetti, and Maria Pia Longhese
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checkpoint ,DNA damage ,double-strand breaks ,Dpb11/TopBP1 ,MRX/MRN ,Rad9/53BP1 ,Biology (General) ,QH301-705.5 - Abstract
Summary: Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection is a two-step process in which an initial short-range step is catalyzed by the Mre11-Rad50-Xrs2 (MRX) complex and limited to the vicinity of the DSB end. Then the two long-range resection Exo1 and Dna2-Sgs1 nucleases extend the resected DNA tracts. How short-range resection is regulated and contributes to checkpoint activation remains to be determined. Here, we show that abrogation of long-range resection induces a checkpoint response that decreases DNA damage resistance. This checkpoint depends on the 9-1-1 complex, which recruits Dpb11 and Rad9 at damaged DNA. Furthermore, the 9-1-1 complex, independently of Dpb11 and Rad9, restricts short-range resection by negatively regulating Mre11 nuclease. We propose that 9-1-1, which is loaded at the leading edge of resection, plays a key function in regulating Mre11 nuclease and checkpoint activation once DSB resection is initiated.
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- 2020
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5. Translating Systems Medicine Into Clinical Practice: Examples From Pulmonary Medicine With Genetic Disorders, Infections, Inflammations, Cancer Genesis, and Treatment Implication of Molecular Alterations in Non-small-cell Lung Cancers and Personalized Medicine
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Julian Pinsolle, Anne McLeer-Florin, Matteo Giaj Levra, Florence de Fraipont, Camille Emprou, Elisa Gobbini, and Anne-Claire Toffart
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non-small-cell lung cancer ,molecular alterations ,next-generation sequencing ,liquid biopsy ,ALK rearrangement ,EGFR mutation ,Medicine (General) ,R5-920 - Abstract
Non-small-cell lung cancers (NSCLC) represent 85% of all lung cancers, with adenocarcinoma as the most common subtype. Since the 2000's, the discovery of molecular alterations including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements together with the development of specific tyrosine kinase inhibitors (TKIs) has facilitated the development of personalized medicine in the management of this disease. This review focuses on the biology of molecular alterations in NSCLC as well as the diagnostic tools and therapeutic alternatives available for each targetable alteration. Rapid and sensitive methods are essential to detect gene alterations, using tumor tissue biopsies or liquid biopsies. Massive parallel sequencing or Next Generation Sequencing (NGS) allows to simultaneously analyze numerous genes from relatively low amounts of DNA. The detection of oncogenic fusions can be conducted using fluorescence in situ hybridization, reverse-transcription polymerase chain reaction, immunohistochemistry, or NGS. EGFR mutations, ALK and ROS1 rearrangements, MET (MET proto-oncogenereceptor tyrosine kinase), BRAF (B-Raf proto-oncogen serine/threonine kinase), NTRK (neurotrophic tropomyosin receptor kinase), and RET (ret proto-oncogene) alterations are described with their respective TKIs, either already authorized or still in development. We have herein paid particular attention to the mechanisms of resistance to EGFR and ALK-TKI. As a wealth of diagnostic tools and personalized treatments are currently under development, a close collaboration between molecular biologists, pathologists, and oncologists is crucial.
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- 2019
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6. Local unwinding of double-strand DNA ends by the MRX complex promotes Exo1 processing activity
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Elisa Gobbini, Jacopo Vertemara, and Maria Pia Longhese
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double-strand break ,exo1 ,mrx ,resection ,s. cerevisiae ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs), which involves different nucleases including the Mre11-Rad50-Xrs2 (MRX) complex and the Exonuclease 1 (Exo1). The characterization of a novel mutation in Mre11 causing accelerated DSB resection has allowed to show that MRX facilitates DNA end processing by Exo1 through local unwinding of double-stranded DNA ends.
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- 2018
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7. Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks.
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Corinne Cassani, Elisa Gobbini, Weibin Wang, Hengyao Niu, Michela Clerici, Patrick Sung, and Maria Pia Longhese
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Biology (General) ,QH301-705.5 - Abstract
The cellular response to DNA double-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals), which recruits the checkpoint kinase Tel1/ATM to DSBs. In Saccharomyces cerevisiae, the role of Tel1 at DSBs remains enigmatic, as tel1Δ cells do not show obvious hypersensitivity to DSB-inducing agents. By performing a synthetic phenotype screen, we isolated a rad50-V1269M allele that sensitizes tel1Δ cells to genotoxic agents. The MRV1269MX complex associates poorly to DNA ends, and its retention at DSBs is further reduced by the lack of Tel1. As a consequence, tel1Δ rad50-V1269M cells are severely defective both in keeping the DSB ends tethered to each other and in repairing a DSB by either homologous recombination (HR) or nonhomologous end joining (NHEJ). These data indicate that Tel1 promotes MRX retention to DSBs and this function is important to allow proper MRX-DNA binding that is needed for end-tethering and DSB repair. The role of Tel1 in promoting MRX accumulation to DSBs is counteracted by Rif2, which is recruited to DSBs. We also found that Rif2 enhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, suggesting that Rif2 can regulate MRX activity at DSBs by modulating ATP-dependent conformational changes of Rad50.
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- 2016
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8. Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity.
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Elisa Gobbini, Matteo Villa, Marco Gnugnoli, Luca Menin, Michela Clerici, and Maria Pia Longhese
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Genetics ,QH426-470 - Abstract
The MRX complex together with Sae2 initiates resection of DNA double-strand breaks (DSBs) to generate single-stranded DNA (ssDNA) that triggers homologous recombination. The absence of Sae2 not only impairs DSB resection, but also causes prolonged MRX binding at the DSBs that leads to persistent Tel1- and Rad53-dependent DNA damage checkpoint activation and cell cycle arrest. Whether this enhanced checkpoint signaling contributes to the DNA damage sensitivity and/or the resection defect of sae2Δ cells is not known. By performing a genetic screen, we identify rad53 and tel1 mutant alleles that suppress both the DNA damage hypersensitivity and the resection defect of sae2Δ cells through an Sgs1-Dna2-dependent mechanism. These suppression events do not involve escaping the checkpoint-mediated cell cycle arrest. Rather, defective Rad53 or Tel1 signaling bypasses Sae2 function at DSBs by decreasing the amount of Rad9 bound at DSBs. As a consequence, reduced Rad9 association to DNA ends relieves inhibition of Sgs1-Dna2 activity, which can then compensate for the lack of Sae2 in DSB resection and DNA damage resistance. We propose that persistent Tel1 and Rad53 checkpoint signaling in cells lacking Sae2 increases the association of Rad9 at DSBs, which in turn inhibits DSB resection by limiting the activity of the Sgs1-Dna2 resection machinery.
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- 2015
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9. Expert consensus on perioperative treatment for non-small cell lung cancer
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Jianchun Duan, Fengwei Tan, Nan Bi, Chun Chen, Ke-Neng Chen, Ying Cheng, Qian Chu, Di Ge, Jie Hu, Yunchao Huang, Tao Jiang, Hao Long, You Lu, Meiqi Shi, Jialei Wang, Qiming Wang, Fan Yang, Nong Yang, Yu Yao, Jianming Ying, Caicun Zhou, Qing Zhou, Qinghua Zhou, Stefano Bongiolatti, Alessandro Brunelli, Alfonso Fiorelli, Elisa Gobbini, Cesare Gridelli, Thomas John, Jae Jun Kim, Steven H. Lin, Giulio Metro, Fabrizio Minervini, Nuria M. Novoa, Dwight H. Owen, Maria Rodriguez, Ichiro Sakanoue, Marco Scarci, Kenichi Suda, Fabrizio Tabbò, Terence Chi Chun Tam, Masanori Tsuchida, Junji Uchino, Luca Voltolini, Jie Wang, and Shugeng Gao
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Oncology - Published
- 2022
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10. Immune Checkpoint Inhibitor Rechallenge and Resumption: a Systematic Review
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Caroline Plazy, Dalil Hannani, and Elisa Gobbini
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Oncology ,Neoplasms ,Humans ,Immune Checkpoint Inhibitors ,Retrospective Studies - Abstract
The reintroduction of immune checkpoint inhibitors (ICIs) after disease progression (rechallenge) or immune-related adverse events (irAEs) recovering (resumption) raises questions in terms of efficacy and safety.Here, we reviewed literature data about ICIs rechallenge/resumption in cancer patients along with their clinical characteristics to explore those factors associated with better outcomes. Heterogenous results were pointed out across rechallenge studies with an overall response rate between 0 and 54%, and a progression free survival ranged from 1.5 to 12.9 months and an overall survival between 6.5 and 23.8 months. Better outcomes have been recorded in patients with good ECOG PS, longer duration of initial ICI, discontinuation reason of initial ICI other than progression, and those who received ICI sequence other than the switch between anti-PD1 and anti-PDL1. Studies about ICI resumption highlighted that certain types of irAEs were more likely to relapse at retreatment. These results suggest that ICI rechallenge/resumption can be an interesting strategy for selected patients.
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- 2022
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11. Immune checkpoint inhibitors and hospitalization at home in France
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Elisa Gobbini, Laure Boisserie Lacroix, Thomas Pierret, Laure Schoutteten, J. Pinsolle, Isabelle Federspiel, Amélie Feyeux, Maurice Pérol, and Anne-Claire Toffart
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Cancer Research ,Treatment response ,medicine.medical_specialty ,Home Environment ,Treatment duration ,Immune checkpoint inhibitors ,Nurses ,Home Care Services, Hospital-Based ,Context (language use) ,Neoplasms ,Surveys and Questionnaires ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,In patient ,Medical prescription ,Immune Checkpoint Inhibitors ,Oncologists ,Home environment ,Health professionals ,business.industry ,Mental Disorders ,Patient Selection ,Age Factors ,Hematology ,General Medicine ,Hospitalization ,Oncology ,Models, Organizational ,Family medicine ,France ,business - Abstract
Summary Context The administration of immune checkpoints inhibitors (ICIs) within hospitalization at home (HaH) organizations is an interesting alternative to conventional care. Three surveys were carried out to describe the different organizational models of French HaHs and criteria used by physicians in patient selection. Methods Three surveys were conducted between April 1 and August 31, 2020. The first one was addressed to all French HaHs, and the two others to public HaHs and oncologists treating patients with solid cancer in the Auvergne-Rhone-Alpes region. Results Overall, 54 French HaHs and 23 oncologists participated to the study. The health professionals involved in the patients’ care were very heterogeneous, although in 92% of cases, the treatment prescription was made by the oncologist. HaH physicians were more involved in clinical assessment the day before treatment (19% vs. 0%), treatment validation (56% vs. 15%), and treatment prescription (19% vs. 0%), while nurses were better equipped (emergency kit available in 81% versus 50% of cases) when HaHs did carry out ICIs compared to when they did not. Most oncologists agreed that age, neuropsychiatric disorders, home environment, as well as treatment duration and good tolerance should be considered in patient selection. ECOG PS status and treatment response were less consensually considered. Conclusion These results highlight the variability in French HaH organizations and patient selection criteria for employing ICIs at home. This study resulted in recommendations for administrating ICIs in HaH settings, which will likely be instrumental in further promoting this activity across France.
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- 2022
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12. Epidemiology of oligometastatic non-small cell lung cancer: results from a systematic review and pooled analysis
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Elisa Gobbini, Jessica Menis, Niccolò Giaj-Levra, Luca Bertolaccini, and Matteo Giaj-Levra
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Oncology ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Incidence (epidemiology) ,Population ,MEDLINE ,non-small cell lung cancer (NSCLC) ,Disease ,Review Article on Oligometastatic NSCLC: Definition and Treatment Opportunities ,medicine.disease ,Internal medicine ,Epidemiology ,medicine ,Stage (cooking) ,Lung cancer ,education ,business - Abstract
Background To describe the incidence and the clinical characteristics of oligometastatic non-small cell lung cancer (NSCLC) patients. Oligometastatic NSCLC is gaining recognition as a clinical condition with a different prognosis compared to multi metastatic disease. Usually, four different scenarios of oligometastatic disease can be described but not epidemiological data are available. To date, it is difficult to delineate an exhaustive epidemiological scenario because no uniform or shared definition of oligometastatic status exists, even though a recent consensus defined synchronous oligometastatic disease as having a maximum of 5 metastases in 3 different organs. Methods A systematic review and a pooled analysis of literature were performed. Article selection was based on the following characteristics: focus on lung cancers; dealing with oligometastatic settings and providing a definition of oligometastatic disease; number of metastatic lesions with or without the number of organs involved; providing some incidence or clinical characteristics of oligometastatic NSCLC patients. Series focusing on a specific single metastatic organ were excluded. The research was launched in MEDLINE (OvidSP) in March 2020. Full articles were individually and collectively read by the authors according to the previous criteria. Each author inspected the reference list included in the eligible articles. If the selection criteria were recognized, the article was reviewed by all authors and then included. Data on patient clinical features were pooled together from 31 articles selected. Results A total number of 31 articles have been selected for the analysis. The following variables were extracted from the publications: (I) number of metastases, (II) number of organs involved, (III) number of patients, (IV) number and percentage of males and females, (V) number and percentage of squamous and non-squamous histology, (VI) T and N status and/or stage of primary disease for oligometastatic setting. The data collected have been analyzed according to the oligometastatic setting. Conclusions Oligometastatic status is globally identified as a different clinical condition from multi metastatic NSCLC, although the clinical characteristics were consistent in the general metastatic population, even with a lower-than-expected TN status. The brain and bones were the most frequent organs involved. Lacking consensus definition, these results must be interpreted cautiously and a prospective evaluation is urgently needed.
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- 2021
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13. How do cells sense DNA lesions?
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Chiara Vittoria Colombo, Elisa Gobbini, Marco Gnugnoli, Maria Pia Longhese, Colombo, C, Gnugnoli, M, Gobbini, E, and Longhese, M
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DNA Replication ,Saccharomyces cerevisiae Proteins ,DNA recombination ,DNA damage ,DNA repair ,DNA, Single-Stranded ,BIO/18 - GENETICA ,Ataxia Telangiectasia Mutated Proteins ,Saccharomyces cerevisiae ,single-stranded DNA ,Protein Serine-Threonine Kinases ,Biology ,DNA damage response ,Biochemistry ,law.invention ,Xenopus laevis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Schizosaccharomyces ,Sense (molecular biology) ,Animals ,Humans ,Phosphorylation ,030304 developmental biology ,0303 health sciences ,Proto-Oncogene Proteins c-ets ,Cell Cycle ,Intracellular Signaling Peptides and Proteins ,DNA replication ,DNA ,Cell cycle ,Cell biology ,Repressor Proteins ,body regions ,ATR ,chemistry ,ATM ,Recombinant DNA ,Exogenous DNA ,030217 neurology & neurosurgery ,DNA Damage ,Signal Transduction - Abstract
DNA is exposed to both endogenous and exogenous DNA damaging agents that chemically modify it. To counteract the deleterious effects exerted by DNA lesions, eukaryotic cells have evolved a network of cellular pathways, termed DNA damage response (DDR). The DDR comprises both mechanisms devoted to repair DNA lesions and signal transduction pathways that sense DNA damage and transduce this information to specific cellular targets. These targets, in turn, impact a wide range of cellular processes including DNA replication, DNA repair and cell cycle transitions. The importance of the DDR is highlighted by the fact that DDR inactivation is commonly found in cancer and causes many different human diseases. The protein kinases ATM and ATR, as well as their budding yeast orthologs Tel1 and Mec1, act as master regulators of the DDR. The initiating events in the DDR entail both DNA lesion recognition and assembly of protein complexes at the damaged DNA sites. Here, we review what is known about the early steps of the DDR.
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- 2020
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14. Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences
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Fabrizio Tabbò, Lucia Anna Muscarella, Elisa Gobbini, Domenico Trombetta, Stefano Castellana, Angelica Rigutto, Domenico Galetta, Evaristo Maiello, Olga Martelli, Marcello Tiseo, Vieri Scotti, Laura Ghilardi, Vanesa Gregorc, Concetta Sergi, Sara Pilotto, Alessandro Del Conte, Federico Cappuzzo, Diego Cortinovis, Giorgia Osman, Claudia Bareggi, Massimo Di Maio, Antonio Rossi, Giulio Rossi, Emilio Bria, Marco Volante, Giorgio Vittorio Scagliotti, Paolo Graziano, Silvia Novello, and Luisella Righi
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Tyrosine kinase inhibitors ,Oncogene Proteins ,Cancer Research ,Lung Neoplasms ,Oncogene Proteins, Fusion ,Fusion variant ,Carcinoma ,Anaplastic lymphoma kinase ,Oncology ,Crizotinib ,Carcinoma, Non-Small-Cell Lung ,Next-generation sequencing ,Chromosomal rearrangement ,Non–small cell lung cancer ,Anaplastic Lymphoma Kinase ,Humans ,Protein Kinase Inhibitors ,RNA ,Retrospective Studies ,Fusion ,Non-Small-Cell Lung - Abstract
Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist.A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes.Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi.Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.
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- 2022
15. Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods
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Felix Bayerl, David A. Bejarano, Giulia Bertacchi, Anne‐Claire Doffin, Elisa Gobbini, Margaux Hubert, Lijian Li, Philippa Meiser, Anna‐Marie Pedde, Wilfried Posch, Luise Rupp, Andreas Schlitzer, Marc Schmitz, Barbara U. Schraml, Stefan Uderhardt, Jenny Valladeau‐Guilemond, Doris Wilflingseder, Viktoria Zaderer, and Jan P. Böttcher
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Immunology ,Immunology and Allergy - Published
- 2023
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16. Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer
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Aurélie Swalduz, Sandra Ortiz-Cuaran, Maurice Pérol, Matteo Giaj Levra, Elisa Gobbini, Pierre Saintigny, Denis Moro-Sibilot, and Anne-Claire Toffart
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Review ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Clinical significance ,Liquid biopsy ,Lung cancer ,Genotyping ,circulating tumor DNA ,liquid biopsy ,business.industry ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Minimal residual disease ,Biomarker (cell) ,Clinical trial ,lung cancer ,030104 developmental biology ,030220 oncology & carcinogenesis ,biomarker ,next-generation sequencing ,business - Abstract
Simple Summary The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. Abstract Tumor genomic profiling has a dramatic impact on the selection of targeted treatment and for the identification of resistance mechanisms at the time of progression. Solid tissue biopsies are sometimes challenging, and liquid biopsies are used as a non-invasive alternative when tissue is limiting. The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. Its potential applications in early disease detection and the response evaluation to radical treatments are promising. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. In addition to available studies demonstrating the clinical relevance of liquid biopsies, there is a need for standardization and well-designed clinical trials to demonstrate its clinical utility.
- Published
- 2020
17. Resection of a DNA Double-Strand Break by Alkaline Gel Electrophoresis and Southern Blotting
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Erika, Casari, Elisa, Gobbini, Michela, Clerici, and Maria Pia, Longhese
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Electrophoresis ,Blotting, Southern ,Saccharomyces cerevisiae Proteins ,DNA, Single-Stranded ,Recombinational DNA Repair ,DNA Breaks, Double-Stranded ,Saccharomyces cerevisiae ,DNA, Fungal ,Deoxyribonucleases, Type II Site-Specific - Abstract
Generation of 3' single-stranded DNA (ssDNA) at the ends of a double-strand break (DSB) is essential to initiate repair by homology-directed mechanisms. Here we describe a Southern blot-based method to visualize the generation of ssDNA at the ends of site-specific DSBs generated in the Saccharomyces cerevisiae genome.
- Published
- 2020
18. The 9-1-1 Complex Controls Mre11 Nuclease and Checkpoint Activation during Short-Range Resection of DNA Double-Strand Breaks
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Chiara Vittoria Colombo, Maria Pia Longhese, Elisa Gobbini, Erika Casari, Diego Bonetti, Gobbini, E, Casari, E, Colombo, C, Bonetti, D, and Longhese, M
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0301 basic medicine ,double-strand break ,Saccharomyces cerevisiae Proteins ,DNA Repair ,DNA damage ,S. cerevisiae ,MRX/MRN ,Saccharomyces cerevisiae ,General Biochemistry, Genetics and Molecular Biology ,Resection ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,checkpoint ,resection ,Homologous Recombination ,lcsh:QH301-705.5 ,Double strand ,double-strand breaks ,Nuclease ,Endodeoxyribonucleases ,biology ,RecQ Helicases ,DNA Helicases ,DNA ,Endonucleases ,Cell biology ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Exodeoxyribonucleases ,lcsh:Biology (General) ,chemistry ,biology.protein ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,Dpb11/TopBP1 ,Rad9/53BP1 ,030217 neurology & neurosurgery ,9-1-1 ,DNA Damage - Abstract
Summary Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection is a two-step process in which an initial short-range step is catalyzed by the Mre11-Rad50-Xrs2 (MRX) complex and limited to the vicinity of the DSB end. Then the two long-range resection Exo1 and Dna2-Sgs1 nucleases extend the resected DNA tracts. How short-range resection is regulated and contributes to checkpoint activation remains to be determined. Here, we show that abrogation of long-range resection induces a checkpoint response that decreases DNA damage resistance. This checkpoint depends on the 9-1-1 complex, which recruits Dpb11 and Rad9 at damaged DNA. Furthermore, the 9-1-1 complex, independently of Dpb11 and Rad9, restricts short-range resection by negatively regulating Mre11 nuclease. We propose that 9-1-1, which is loaded at the leading edge of resection, plays a key function in regulating Mre11 nuclease and checkpoint activation once DSB resection is initiated.
- Published
- 2020
19. Literature meta-analysis about the efficacy of re-challenge with PD-1 and PD-L1 inhibitors in cancer patients
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Elisa Gobbini, Matteo Giaj Levra, Julie Charles, Denis Moro-Sibilot, Anne-Claire Toffart, Marie-Thérèse Leccia, CHU Grenoble, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Léon Bérard [Lyon], and CCSD, Accord Elsevier
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,[SDV]Life Sciences [q-bio] ,Programmed Cell Death 1 Receptor ,Immune checkpoint inhibitor ,B7-H1 Antigen ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,Re challenge ,Melanoma ,Aged, 80 and over ,biology ,Hazard ratio ,Hematology ,General Medicine ,Middle Aged ,Progression-Free Survival ,3. Good health ,[SDV] Life Sciences [q-bio] ,Treatment Outcome ,030220 oncology & carcinogenesis ,Meta-analysis ,Toxicity ,Retreatment ,Female ,Anti-programmed cell death ligand 1 ,Adult ,medicine.medical_specialty ,Re-challenge ,03 medical and health sciences ,Young Adult ,Internal medicine ,PD-L1 ,Anti-programmed cell death protein 1 ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Lung cancer ,Aged ,business.industry ,Solid cancer ,Cancer ,medicine.disease ,030104 developmental biology ,biology.protein ,business - Abstract
Summary Introduction Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy. Methods Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/anti-PD-L1 were collected. Results Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, P = 4.10−4) and disease control rates (73% versus 52%, P = 7.10−3) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found (P = 3.10−1). The PFS upon the first ICPi (PFS1) was longer than after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, P = 2.10−3). A longer PFSR was obtained in patients with a longer PFS1 (P = 6.10−3), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, P = 2.10−3), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, P = 1.10−3). Discussion Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period.
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- 2020
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20. Literature meta-analysis about the efficacy of anti-programmed death protein 1 and anti-programmed death ligand 1 re-challenge in cancer patients
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Julie Charles, Elisa Gobbini, Matteo Giaj Levra, Marie-Thérèse Leccia, Denis Moro-Sibilot, and Anne-Claire Toffart
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business.industry ,Meta-analysis ,Cancer research ,Medicine ,Cancer ,Re challenge ,Ligand (biochemistry) ,business ,medicine.disease ,Programmed death - Abstract
Background Immune checkpoint inhibitor (ICPis) re-challenge could be an attractive therapeutic option considering its good safety profile. However, little data is available regarding anti-PD-1/anti-PD-L1 retreatment. We conducted a meta-analysis focusing on outcomes of solid cancer patients performing this strategy. Methods Fourteen full papers involving 74 patients were included. Individual data about best response or progression-free survival (PFS) upon the first and second course of anti-PD-1/ anti-PD-L1 were collected. Results Non-small-cell lung cancer (53%) and melanoma (34%) were the most represented cancers. Higher objective response (46% versus 24%, p = 4.10 -4 ) and disease control rates (73% versus 52%, p = 7.10 -3 ) were obtained upon the first ICPi course compared to re-challenge. No association between responses obtained with the two ICPis courses was found ( p = 3.10 -1 ). The PFS upon the first ICPi (PFS1) was longer than that after re-challenge (PFSR) (6.6 versus 2.8 months, hazard ratio (HR) 0.57, p = 2.10 -3 ). A longer PFSR was obtained in patients with a longer PFS1 ( p = 6.10 -3 ), in those who discontinued the first ICPi due to toxicity or per protocol (8.8 versus 2.1 months if disease progression occurs, p = 2.10 -3 ), and in those not receiving intercalated treatment between the two ICPis (6.6 versus 2.1 months for the treated ones, p = 1.10 -3 ). Conclusion Anti-PD-1/anti-PD-L1 re-challenge showed interesting clinical activity in selected patients, mainly in those achieving a long-term response upon the first ICPi course, that do not discontinue therapy because of disease progression, or that are able to keep a treatment-free period.
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- 2020
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21. Molecular profiling in Italian patients with advanced non-small-cell lung cancer: An observational prospective study
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Vieri Scotti, Salvatore Pisconti, Paolo Graziano, Evaristo Maiello, Ferdinando Riccardi, F. Arizio, Emilio Bria, Domenico Galetta, Giulio Rossi, Marcello Tiseo, Diego Cortinovis, Silvia Novello, Lucio Buffoni, Anna Ceribelli, Tindara Franchina, Maria Rita Migliorino, Angelo Delmonte, Elisa Gobbini, Paola Bordi, Vanesa Gregorc, Massimo Di Maio, Annamaria Catino, and Antonio Rossi
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Adult ,Male ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,Afatinib ,Kaplan-Meier Estimate ,medicine.disease_cause ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,ROS1 ,Humans ,Molecular Targeted Therapy ,Prospective Studies ,030212 general & internal medicine ,Prospective cohort study ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Gene Rearrangement ,Crizotinib ,business.industry ,Gene Expression Profiling ,Middle Aged ,medicine.disease ,Surgery ,Molecular profiling ,ALK inhibitor ,Treatment Outcome ,Italy ,030220 oncology & carcinogenesis ,Mutation ,Female ,KRAS ,Transcriptome ,business ,medicine.drug - Abstract
Objectives Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. Materials and methods This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients’ outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). Results and conclusion Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62–10.0), median PFS1 was 4.61 months (95%CI 4.31–4.84) and median PFS2 was 2.76 months (95%CI 2.57–3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line.
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- 2017
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22. Immune Checkpoint Inhibitors Rechallenge Efficacy in Non-Small-Cell Lung Cancer Patients
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Chantal Decroisette, Etienne Giroux Leprieur, Olivier Molinier, Elisa Gobbini, Catherine Dubos, Denis Moro-Sibilot, Eric Dansin, Jean-Baptiste Assié, Dahna Coupez, Remi Veillon, Boris Duchemann, Anne Claire Toffart, Valérie Gounant, Nouha Chaabane, Matteo Giaj Levra, Laura Mezquita, François-Roger Vanel, Virginie Westeel, Youssef Oulkhouir, Vincent Alcazer, Michael Duruisseaux, A. Canellas, Fabrice Barlesi, Maurice Pérol, Myriam Delaunay, Florian Guisier, Pierre Fournel, Hélène Babey, and Catherine Daniel
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Lung Neoplasms ,Adenocarcinoma of Lung ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,Immune Checkpoint Inhibitors ,Aged ,Retrospective Studies ,Performance status ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Confidence interval ,Discontinuation ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Toxicity ,Retreatment ,Carcinoma, Squamous Cell ,Female ,business ,Follow-Up Studies - Abstract
Background Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non–small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This retrospective observational multicenter national study explored the efficacy of anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes. Patients and Methods We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively. Results The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10−1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis. Conclusion Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.
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- 2020
23. Real-world outcomes according to treatment strategies in ALK-rearranged non-small-cell lung cancer (NSCLC) patients: an Italian retrospective study
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A. Del Conte, Fabrizio Tabbò, Emilio Bria, Sara Pilotto, Evaristo Maiello, Domenico Galetta, F.L. Cecere, Rita Chiari, Concetta Sergi, Frederico Cappuzzo, P. Pizzutillo, F. Riccardi, Marcello Tiseo, G. Borra, Vieri Scotti, Paola Bordi, Olga Martelli, Claudia Bareggi, Giulio Rossi, L. Ghilardi, Paolo Graziano, C. Casartelli, Elisa Gobbini, P. Rizzo, Antonio Rossi, M. Di Maio, Vanesa Gregorc, Angelo Delmonte, G. Osman, Diego Cortinovis, and Silvia Novello
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0301 basic medicine ,Oncology ,ALK inhibitors ,Male ,Cancer Research ,Lung Neoplasms ,non-small cell lung cancer (NSCLC) ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Non-Small-Cell Lung ,Aged, 80 and over ,Gene Rearrangement ,education.field_of_study ,General Medicine ,Middle Aged ,Treatment Outcome ,Italy ,030220 oncology & carcinogenesis ,Female ,Lung cancer ,medicine.drug ,Adult ,medicine.medical_specialty ,Brigatinib ,Population ,03 medical and health sciences ,Young Adult ,Crizotinib ,Internal medicine ,Sequence ,medicine ,Humans ,education ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Carcinoma ,Gene rearrangement ,medicine.disease ,Lorlatinib ,030104 developmental biology ,business - Abstract
Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received. We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions. After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9–11.2] and 11.1 months [CI 95% 9.2–13.8], respectively, while TTF were 10.2 [CI 95% 8.5–12.6] and 11.9 months [CI 95% 9.7–17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3–33.7] in PFS and 30.4 months [CI 95% 24.7–34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8–54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0–73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6–NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3–34.0)] (P
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- 2019
24. Current opinions in immune checkpoint inhibitors rechallenge in solid cancers
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Denis Moro-Sibilot, Anne-Claire Toffart, M. Giaj Levra, Julie Charles, Marie-Thérèse Leccia, Elisa Gobbini, CHU Grenoble, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and CCSD, Accord Elsevier
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Immune checkpoint inhibitors ,[SDV]Life Sciences [q-bio] ,Therapeutic algorithm ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Immunologic Factors ,Melanoma ,T lymphocyte antigen ,business.industry ,Hematology ,medicine.disease ,Alternative treatment ,3. Good health ,[SDV] Life Sciences [q-bio] ,Clinical trial ,Clinical Practice ,030104 developmental biology ,Tolerability ,030220 oncology & carcinogenesis ,Immunotherapy ,business - Abstract
Immune checkpoint inhibitors (ICI) completely upset the therapeutic algorithm of several type of solid cancer conferring in some patients a long clinical benefit with an acceptable toxicity. ICI rechallenge is an attractive option being a palliative chemotherapy the only alternative treatment in most of cases. Despite this strategy recently entered into the clinical practice, no widely recognized recommendation is currently available to select the good candidates. Anti-Cytotoxic T Lymphocyte Antigen 4 (Anti-CTLA4) rechallenge and a sequential administration of anti-CTLA4 and anti-Programmed cell Death protein 1 (anti-PD1) or Anti-Programmed Death Ligand 1 (anti-PDL1) agents have been explored in melanoma patients in several clinical trials while the anti-PD1/anti-PDL1 rechallenge has been little investigated. Here we performed a literature revision about efficacy and tolerability of ICI rechallenge across solid tumors also focusing on inclusion criteria used into clinical trials.
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- 2019
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25. Human Tumor-Infiltrating Dendritic Cells: From In Situ Visualization to High-Dimensional Analyses
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Margaux Hubert, Elisa Gobbini, Nathalie Bendriss-Vermare, Christophe Caux, and Jenny Valladeau-Guilemond
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immune signatures ,single cell RNA-seq ,Review ,dendritic cells ,prognosis ,RNA-seq ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,cytometry ,lcsh:RC254-282 - Abstract
The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers.
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- 2019
26. Coupling end resection with the checkpoint response at DNA double-strand breaks
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Diego Bonetti, Matteo Villa, Corinne Cassani, Elisa Gobbini, Maria Pia Longhese, Villa, M, Cassani, C, Gobbini, E, Bonetti, D, and Longhese, M
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0301 basic medicine ,Saccharomyces cerevisiae Proteins ,Cell cycle checkpoint ,genetic processes ,Saccharomyces cerevisiae ,BIO/18 - GENETICA ,Biology ,Models, Biological ,MRX ,Resection ,Nuclease ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Mec1 ,DNA Breaks, Double-Stranded ,Molecular Biology ,Pharmacology ,Genetics ,Double strand ,Tel1 ,fungi ,Cell Cycle Checkpoints ,Cell Biology ,G2-M DNA damage checkpoint ,Endonucleases ,biology.organism_classification ,Cell biology ,Coupling (electronics) ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,chemistry ,Double-strand break ,health occupations ,Molecular Medicine ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,030217 neurology & neurosurgery ,DNA - Abstract
DNA double-strand breaks (DSBs) are a nasty form of damage that needs to be repaired to ensure genome stability. The DSB ends can undergo a strand-biased nucleolytic processing (resection) to generate 3′-ended single-stranded DNA (ssDNA) that channels DSB repair into homologous recombination. Generation of ssDNA also triggers the activation of the DNA damage checkpoint, which couples cell cycle progression with DSB repair. The checkpoint response is intimately linked to DSB resection, as some checkpoint proteins regulate the resection process. The present review will highlight recent works on the mechanism and regulation of DSB resection and its interplays with checkpoint activation/inactivation in budding yeast.
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- 2016
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27. Advances and Therapeutic Perspectives in Extended-Stage Small-Cell Lung Cancer
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Elisa Gobbini, Thomas Pierret, Denis Moro-Sibilot, Anne-Claire Toffart, and Matteo Giaj Levra
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Improved survival ,Review ,extended small cell lung cancer ,Aggressive disease ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,target agents ,medicine ,In patient ,Stage (cooking) ,Intensive care medicine ,Predictive biomarker ,Chemotherapy ,business.industry ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,respiratory tract diseases ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,immunotherapy ,Non small cell ,business - Abstract
Simple Summary Extended small cell lung cancer (ED-SCLC) remains an aggressive disease without major advances in the last 20 years. Recently, new therapies have eventually improved the outcomes of these patients, completely overturning their management. The objective of this review is to describe the most recent advances in ED-SCLC treatment, starting from immunotherapy as monotherapy or in combination with chemotherapy. Despite the proved clinical activity of this strategy, few patients achieve a long-term benefit and further studies are needed to find useful biomarkers. Furthermore, we review the most promising target agents and chemotherapies currently under investigation. Therefore, this proposal provides a comprehensive overview of available treatment strategies for ED-SCLC patients, highlighting their strengths and weaknesses. Abstract Extended small cell lung cancer (ED-SCLC) is a very aggressive disease, characterized by rapid growth and an early tendency to relapse. In contrast to non-small cell lung cancer, no therapeutic innovation has improved survival in patients with ED-SCLC over the past 20 years. Recently, immunotherapy has shown an important role in the management of these patients, emerging as the treatment of first choice in combination with chemotherapy and completely changing the therapeutic paradigm. However, patients’ selection for this strategy is still challenging due to a lack of reliable predictive biomarkers. Conversely, the immunotherapy efficacy beyond the first line is pretty disappointing and innovative chemotherapies or target agents seem to be more promising in this setting. Some of them are also under evaluation as an upfront strategy and they will probably change the treatment algorithm in the next future. This proposal provides a comprehensive overview of available treatment strategies for ED-SCLC patients, highlighting their strengths and weaknesses.
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- 2020
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28. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer
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Jenny Valladeau-Guilemond, Elisa Gobbini, Christophe Sajous, Vincent Ollion, Céline Rodriguez, Olivier Tredan, Margaux Hubert, Isabelle Treilleux, Marc Dalod, Justine Berthet, Bertrand Dubois, Christophe Caux, Janice Kielbassa, Coline Couillault, Anne-Claire Doffin, Thien-Phong Vu Manh, Nathalie Bendriss-Vermare, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Institut de Recherche en Mathématiques, Interactions et Applications (Labex_IRMIA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), SERM, INCA (PLBIO INCa_4508and PLBIO INCa_11155), ANRS, ARC, Ligue contre le Cancer (Régionale Auvergne-Rhône-Alpes et Saône-et-Loire, Comité de la Savoie), and la Région Rhône-Alpes Auvergne (IRICE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Fondation Synergie Lyon Cancer [Lyon]
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0301 basic medicine ,Chemokine ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Immunology ,Breast Neoplasms ,Interferon Lambda ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Breast cancer ,Interferon ,Medicine ,Cytotoxic T cell ,Humans ,biology ,business.industry ,General Medicine ,Immunotherapy ,Dendritic Cells ,medicine.disease ,Immunity, Innate ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,TLR3 ,biology.protein ,Cancer research ,Female ,Interferons ,business ,Conventional Dendritic Cell ,medicine.drug - Abstract
International audience; Dendritic cells play a key role in the orchestration of antitumor immune responses. The cDC1 (conventional dendritic cell 1) subset has been shown to be essential for antitumor responses and response to immunotherapy, but its precise role in humans is largely unexplored. Using a multidisciplinary approach, we demonstrate that human cDC1 play an important role in the antitumor immune response through their capacity to produce type III interferon (IFN-λ). By analyzing a large cohort of breast primary tumors and public transcriptomic datasets, we observed specific production of IFN-λ1 by cDC1. In addition, both IFN-λ1 and its receptor were associated with favorable patient outcomes. We show that IFN-III promotes a TH1 microenvironment through increased production of IL-12p70, IFN-γ, and cytotoxic lymphocyte–recruiting chemokines. Last, we showed that engagement of TLR3 is a therapeutic strategy to induce IFN-III production by tumor-associated cDC1. These data provide insight into potential IFN- or cDC1-targeting antitumor therapies.
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- 2018
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29. The <scp>MRX</scp> complex regulates Exo1 resection activity by altering <scp>DNA</scp> end structure
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Maria Pia Longhese, Patrick Sung, Corinne Cassani, Elisa Gobbini, Fabiana Mambretti, Weibin Wang, Erika Casari, Giuseppe Zampella, Renata Tisi, Jacopo Vertemara, Gobbini, E, Cassani, C, Vertemara, J, Wang, W, Mambretti, F, Casari, E, Sung, P, Tisi, R, Zampella, G, and Longhese, M
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0301 basic medicine ,Saccharomyces cerevisiae Proteins ,genetic processes ,Mutant ,Saccharomyces cerevisiae ,Biology ,Exo1 ,MRX ,General Biochemistry, Genetics and Molecular Biology ,Resection ,03 medical and health sciences ,chemistry.chemical_compound ,Protein Domains ,DNA Breaks, Double-Stranded ,resection ,DNA, Fungal ,Sae2 ,Molecular Biology ,Nuclease ,Endodeoxyribonucleases ,General Immunology and Microbiology ,General Neuroscience ,fungi ,Articles ,double‐strand break ,Cell biology ,enzymes and coenzymes (carbohydrates) ,Exodeoxyribonucleases ,030104 developmental biology ,MRX complex ,chemistry ,Multiprotein Complexes ,health occupations ,biology.protein ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,Function (biology) ,DNA - Abstract
Homologous recombination is triggered by nucleolytic degradation (resection) of DNA double‐strand breaks (DSBs). DSB resection requires the Mre11‐Rad50‐Xrs2 (MRX) complex, which promotes the activity of Exo1 nuclease through a poorly understood mechanism. Here, we describe the Mre11‐R10T mutant variant that accelerates DSB resection compared to wild‐type Mre11 by potentiating Exo1‐mediated processing. This increased Exo1 resection activity leads to a decreased association of the Ku complex to DSBs and an enhanced DSB resection in G1, indicating that Exo1 has a direct function in preventing Ku association with DSBs. Molecular dynamics simulations show that rotation of the Mre11 capping domains is able to induce unwinding of double‐strand DNA (dsDNA). The R10T substitution causes altered orientation of the Mre11 capping domain that leads to persistent melting of the dsDNA end. We propose that MRX creates a specific DNA end structure that promotes Exo1 resection activity by facilitating the persistence of this nuclease on the DSB ends, uncovering a novel MRX function in DSB resection.
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- 2018
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30. Is there a room for immune checkpoint inhibitors in early stage non-small cell lung cancer?
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Matteo Giaj Levra and Elisa Gobbini
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Adoptive cell transfer ,Chemotherapy ,030102 biochemistry & molecular biology ,business.industry ,medicine.medical_treatment ,Immunotherapy ,Review Article ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,Immune system ,Internal medicine ,medicine ,Adjuvant therapy ,business ,Lung cancer ,Adjuvant ,Survival rate - Abstract
Early non-small cell lung cancer (NSCLC) represents 16% of all new NSCLC at diagnosis with a 5-year survival rate of about 60%. Surgical intervention and adjuvant platinum-based chemotherapy represent the cornerstone treatments, but no significant advances have been achieved since several decades in term of relapse rate reduction or survival improvement. Immunotherapy represents an appealing strategy considering the acceptable toxicity profile but, despite the awesome changing recently introduced in the locally advanced and metastatic setting, its role in early NSCLC is not clear yet. In the past few years, two strategies have been investigated to improve the early NSCLC outcomes eliciting the anti-tumour immune response: tumour vaccines and adoptive cellular therapies. However, none of them provided convincing results. Preclinical and clinical data supported the prognostic role of immune checkpoints in resected NSCLC even if they did not show a clear predictive value for adjuvant treatment. However, some preliminary data about safety and efficacy of neo-adjuvant immune checkpoint inhibitors encourage further investigation of their potential role as monotherapy or as part of a multimodal strategy. Then, even if no significant progress has been done in early NSCLC treatment until today, checkpoint inhibitors can open the door to a new strategy in this setting.
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- 2018
31. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort
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Laurence Vanlemmens, Marc Debled, Christian Cailliot, Elisa Gobbini, Thomas Bachelot, Monia Ezzalfani, Christelle Jouannaud, Suzette Delaloge, Magali Lacroix-Triki, Anne Patsouris, Thierry Petit, Simone Mathoulin-Pélissier, Veronique Lorgis, William Jacot, Marie Ange Mouret-Reynier, Mathieu Robain, C. Lefeuvre-Plesse, Florence Dalenc, Audrey Lardy Cleaud, Etienne Brain, Christelle Levy, David Pérol, C. Courtinard, Véronique Diéras, Marianne Leheurteur, Lionel Uwer, Anthony Gonçalves, Jean Marc Ferrero, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute Curie, Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale supérieure d'architecture de Toulouse (ENSA Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Jean Godinot, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département de biologie et pathologie médicales [Gustave Roussy], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Haute Normandie-CRLCC Henri Becquerel, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Center Oscar Lambret, CRLCC Oscar Lambret, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie - Saint Cloud (ICSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER
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Adult ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Time Factors ,Receptor, ErbB-2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Cancer Survivors ,Risk Factors ,HER2 ,Internal medicine ,polycyclic compounds ,Overall survival ,Biomarkers, Tumor ,Medicine ,Humans ,030212 general & internal medicine ,Neoplasm Metastasis ,skin and connective tissue diseases ,Aged ,Retrospective Studies ,Subtypes ,Aged, 80 and over ,business.industry ,Time trends ,Hazard ratio ,Middle Aged ,Metastatic breast cancer ,medicine.disease ,Confidence interval ,3. Good health ,Treatment Outcome ,Oncology ,Receptors, Estrogen ,030220 oncology & carcinogenesis ,Cohort ,Observational study ,Female ,France ,business ,Receptors, Progesterone - Abstract
Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.
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- 2018
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32. MA08.02 Durvalumab Impact in the Treatment Strategy of Stage III Non-Small Cell Lung Cancer (NSCLC): An EORTC Young Investigator Lung Cancer Group Survey
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Jessica Menis, Nicolas Girard, Corinne Faivre-Finn, A. Pochesci, M. Giaj Levra, N. Giaj Levra, Laurent Greillier, Thierry Berghmans, A.M. Dingemans, Silvia Novello, Mary O'Brien, Martin Reck, Antonin Levy, Alessio Bruni, Benjamin Besse, Lizza E.L. Hendriks, Sylvie Lantuejoul, Elisa Gobbini, John G. Edwards, J. Benet, and Baktiar Hasan
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Durvalumab ,business.industry ,Internal medicine ,medicine ,Treatment strategy ,Lung cancer ,medicine.disease ,business ,Stage III Non-Small Cell Lung Cancer - Published
- 2019
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33. P1.14-26 ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma
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Frederico Cappuzzo, Luisella Righi, Paola Bordi, Vieri Scotti, Olga Martelli, Antonio Bonfitto, Domenico Galetta, A. Del Conte, M. Di Maio, D. Cortinovis, Claudia Bareggi, Elisa Gobbini, Silvia Novello, Fabrizio Tabbò, E. Bria, A. Rigutto, L. Ghilardi, Paolo Graziano, Vanesa Gregorc, Sara Pilotto, Marco Volante, M. Tiseo, G. Osman, G.B. Rossi, G.V. Scagliotti, Domenico Trombetta, Evaristo Maiello, Concetta Sergi, Lucia Anna Muscarella, and Aroldo Rossi
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Pulmonary and Respiratory Medicine ,Lung ,medicine.anatomical_structure ,Oncology ,business.industry ,medicine ,ALK-Positive ,Cancer research ,Adenocarcinoma ,RNA-Seq ,business ,medicine.disease - Published
- 2019
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34. Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer
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Silvia Novello, Massimo Di Maio, Massimo Aglietta, Teresa Severina Di Stefano, Elisa Gobbini, F. Arizio, Roberta Matocci, Rita Chiari, P. Petrillo, Alessandro Di Costanzo, Valentina Polo, Isabella Sperduti, Sara Pilotto, Celeste Cagnazzo, Emilio Bria, Domenico Galetta, and Giulia Pasello
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Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Financial Management ,Accrual ,viruses ,Bureaucratic procedures ,Patient accrual ,Time saving ,Medical Oncology ,Urethane ,Timelines ,CRO ,Clinical trials ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Academies and Institutes ,Clinical Trials as Topic ,Humans ,Italy ,Research Support as Topic ,Retrospective Studies ,Contract Services ,Sodium Fluoride ,medicine ,030212 general & internal medicine ,Lung cancer ,business.industry ,Retrospective cohort study ,medicine.disease ,Clinical trial ,Oncology ,Contract research organization ,Median time ,030220 oncology & carcinogenesis ,business - Abstract
Introduction Contract research organization (CRO) support is largely included in clinical trial management, although its effect in terms of time savings and benefit has not yet been quantified. We performed a retrospective multicenter analysis of lung cancer trials to explore differences in term of trial activation timelines and accrual for studies with and without CRO involvement. Materials and Methods Results regarding study timelines from feasibility data to first patient enrollment were collected from 7 Italian thoracic oncology departments. The final accruals (screened/enrolled patients) are reported. We considered CRO/sponsor-administered and CRO-free trials according to who was responsible for the management of the crucial setup phases. Results Of 113 trials, 62 (54.9%) were CRO-administered, 34 (30.1%) were sponsor-administered, and 17 (15.0%) were CRO-free. The median time from feasibility invitation to documentation obtainment was 151 days in the CRO-administered trials versus 128 in the sponsor-administered and 120 in the CRO-free trials. The time from document submission to contract signature was 142 days in the CRO-administered versus 128 in the sponsor-administered and 132 in the CRO-free trials. The time from global accrual opening to first patient enrollment was 247 days for the CRO-administered versus 194 in the sponsor-administered and 151 in the CRO-free trials. No significant differences were observed in terms of the median overall timeline: 21 months in the CRO-administered, 15 in the sponsor-administered, and 18 months in the CRO-free studies (P = .29). Conclusion Although no statistically significant differences were identified, the results of our analysis support the idea that bureaucratic procedures might require more time in CRO-administered trials than in sponsor-administered and CRO-free studies. This bureaucratic delay could negatively affect Italian patients’ screening and enrollment compared with other countries.
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- 2018
35. Escape of Sgs1 from Rad9 inhibition reduces the requirement for Sae2 and functional <scp>MRX</scp> in <scp>DNA</scp> end resection
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Matteo Villa, Giulia Tedeschi, Diego Bonetti, Maria Pia Longhese, Corinne Cassani, Elisa Gobbini, Bonetti, D, Villa, M, Gobbini, E, Cassani, C, Tedeschi, G, and Longhese, M
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double-strand break ,Saccharomyces cerevisiae Proteins ,genetic processes ,Mutant ,Saccharomyces cerevisiae ,BIO/18 - GENETICA ,Cell Cycle Proteins ,Biology ,Models, Biological ,Biochemistry ,Resection ,chemistry.chemical_compound ,Genetic ,Rad9 ,Genetics ,resection ,Molecular Biology ,Sgs1 ,Endodeoxyribonucleases ,RecQ Helicases ,Scientific Reports ,fungi ,Recombinational DNA Repair ,Endonucleases ,biology.organism_classification ,Molecular biology ,Cell biology ,DNA-Binding Proteins ,enzymes and coenzymes (carbohydrates) ,Exodeoxyribonucleases ,MRX complex ,chemistry ,Multiprotein Complexes ,Extensive resection ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,DNA - Abstract
Homologous recombination requires nucleolytic degradation (resection) of DNA double-strand break (DSB) ends. In Saccharomyces cerevisiae, the MRX complex and Sae2 are involved in the onset of DSB resection, whereas extensive resection requires Exo1 and the concerted action of Dna2 and Sgs1. Here, we show that the checkpoint protein Rad9 limits the action of Sgs1/Dna2 in DSB resection by inhibiting Sgs1 binding/persistence at the DSB ends. When inhibition by Rad9 is abolished by the Sgs1-ss mutant variant or by deletion of RAD9, the requirement for Sae2 and functional MRX in DSB resection is reduced. These results provide new insights into how early and long-range resection is coordinated. Synopsis The checkpoint protein Rad9 inhibits the Sgs1/Dna2 long-range resection machinery and thereby increases the requirement for MRX/Sae2 activities in DSB resection. The Sgs1-ss mutant variant suppresses the sensitivity to DNA damaging agents and the resection defect of sae2 cells. Rad9 limits the action of Sgs1/Dna2 in DSB resection by inhibiting Sgs1 binding/persistence at the DSB ends. The escape of Sgs1 from Rad9 inhibition reduces the requirement for Sae2 and functional MRX in DSB resection. The checkpoint protein Rad9 inhibits the Sgs1/Dna2 long-range resection machinery and thereby increases the requirement for MRX-Sae2 activities in DSB resection.
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- 2015
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36. Structurally distinct Mre11 domains mediate MRX functions in resection, end-tethering and DNA damage resistance
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Antonio Marsella, Giuseppe Zampella, Maria Pia Longhese, Renata Tisi, Weibin Wang, Corinne Cassani, Elisa Gobbini, Jacopo Vertemara, Patrick Sung, Cassani, C, Gobbini, E, Vertemara, J, Wang, W, Marsella, A, Sung, P, Tisi, R, Zampella, G, and Longhese, M
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0301 basic medicine ,Models, Molecular ,DNA Repair ,Double-Strand-Break ,Genome Integrity, Repair and Replication ,medicine.disease_cause ,Exo1 ,chemistry.chemical_compound ,DNA Breaks, Double-Stranded ,Endodeoxyribonucleases ,Mutation ,Topoisomerase-I ,Fungal genetics ,Cell biology ,biological phenomena, cell phenomena, and immunity ,medicine.drug ,Saccharomyces cerevisiae Proteins ,DNA repair ,DNA damage ,Nuclease Activitie ,Antineoplastic Agents ,Phleomycins ,Saccharomyces cerevisiae ,Biology ,03 medical and health sciences ,Protein Domains ,Drug Resistance, Fungal ,Genetics ,medicine ,Saccharomyces-Cerevisiae ,Sae2 ,DNA Helicases ,Complex Function ,Endonucleases ,Recombination ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Exodeoxyribonucleases ,chemistry ,Rad50 ,Multiprotein Complexes ,biology.protein ,Camptothecin ,Protein Multimerization ,DNA ,Repair - Abstract
Sae2 cooperates with the Mre11–Rad50-Xrs2 (MRX) complex to initiate resection of DNA double-strand breaks (DSBs) and to maintain the DSB ends in close proximity to allow their repair. How these diverse MRX-Sae2 functions contribute to DNA damage resistance is not known. Here, we describe mre11 alleles that suppress the hypersensitivity of sae2Δ cells to genotoxic agents. By assessing the impact of these mutations at the cellular and structural levels, we found that all the mre11 alleles that restore sae2Δ resistance to both camptothecin and phleomycin affect the Mre11 N-terminus and suppress the resection defect of sae2Δ cells by lowering MRX and Tel1 association to DSBs. As a consequence, the diminished Tel1 persistence potentiates Sgs1-Dna2 resection activity by decreasing Rad9 association to DSBs. By contrast, the mre11 mutations restoring sae2Δ resistance only to phleomycin are located in Mre11 C-terminus and bypass Sae2 function in end-tethering but not in DSB resection, possibly by destabilizing the Mre11–Rad50 open conformation. These findings unmask the existence of structurally distinct Mre11 domains that support resistance to genotoxic agents by mediating different processes.
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- 2017
37. Rechallenge avec les inhibiteurs des points de contrôle immunitaires (ICPis) : issues cliniques dans une cohorte nationale française de patients atteints d’un cancer bronchique non à petites cellules (CBNPC)
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Laura Mezquita, E. Giroux Leprieur, F.R. Vanel, Jean-Baptiste Assié, M. Giaj Levra, Radj Gervais, Olivier Molinier, D. Coupez, Florian Guisier, Valérie Gounant, Pierre Fournel, B. Duchemann, Chantal Decroisette, Fabrice Barlesi, Anne-Claire Toffart, D. Catherine, Maurice Pérol, Eric Dansin, D. Moro-Sibilot, A. Canellas, N. Chaabane, Michael Duruisseaux, Myriam Delaunay, Elisa Gobbini, Youssef Oulkhouir, Remi Veillon, Virginie Westeel, and H. Babey
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Pulmonary and Respiratory Medicine - Abstract
Introduction Les ICPis ont profondement modifie l’algorithme therapeutique du CBNPC au cours des dernieres annees. Malheureusement, la majorite des patients connaissent une progression de la maladie. Le rechallenge avec ICPi pourrait etre une option attrayante, mais aucune donnee a l’appui de cette strategie n’est disponible. Nous presentons les Resultats d’une cohorte de patients ayant recu un rechallenge par ICPi. Methodes Nous avons recueilli retrospectivement les donnees de 144 patients atteints de CBNPC avance (diagnostic entre 2010–2018) parmi 26 centres francais. Les patients ont recu le rechallenge avec ICPi apres au moins 12 semaines d’arret en raison d’une toxicite, progression ou decision clinique. La survie sans progression (SSP) et la survie globale (SG) ont ete calculees a partir du debut du premier ou de la deuxieme ICPi jusqu’a la progression de la maladie (SSP1 ; SSP2) et le deces ou le dernier suivi (SG1 ; SG2) respectivement. Resultats L’âge median etait de 63 ans, la plupart etaient des hommes (67 %), fumeurs (87 %), adenocarcinomes (62 %), au stade IV au moment du diagnostic (66 %). La plupart des patients ont recu le premier ICPi en premiere/deuxieme ligne (66 %) et le deuxieme ICPi en troisieme ligne ou plus tard (79 %). La meilleure reponse au cours du deuxieme ICPi n’etait pas correlee a celle obtenue lors du premier (p = 0,149). Les SSP1 et SSP2 medianes etaient de 13 et de 4,4 mois respectivement. La SSP2 etait plus longue chez les patients ayant abandonne le premier ICPi pour une decision clinique (6,5 mois) ou toxicite (5,8 mois), comparativement a ceux qui ont arrete pour une progression de la maladie (2,9 mois) (p = 0,021), et chez ceux qui n’ont pas recu une chimiotherapie entre les deux ICPis (5,8 mois) comparativement a ceux qui l’ont recue (3,0 mois) (p = 0,002). La SG1 mediane etait de 3,3 ans sans difference selon la raison d’arret du premier ICP (p = 0,266). La SG2 mediane etait de 1,5 ans et etait plus longue chez les patients ayant abandonne le premier ICPi pour toxicite (2,1 ans) comparativement a ceux qui ont arrete pour progression de la maladie (1 an) ou pour decision clinique (1,5 ans) (p = 0,031). Ni la SG1 ni la SG2 n’ont ete affectes par les traitements recus entre les deux ICPis (p = 0,345 et p = 0,117 respectivement). Conclusion La reprise de l’ICPi pourrait etre une option utile, principalement chez les patients qui arretent le premier ICPi pour toxicite ou sur decision clinique et chez ceux qui ont eu un intervalle libre entre les deux ICPi.
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- 2020
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38. MA26.02 Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study
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Vieri Scotti, Elisa Gobbini, G.B. Rossi, A. Del Conte, Claudia Bareggi, Angelo Delmonte, Vanesa Gregorc, Paola Bordi, Olga Martelli, Evaristo Maiello, Sara Pilotto, Claudio Dazzi, Concetta Sergi, G. Osman, M. Di Maio, F.L. Cecere, G. Borra, F. Riccardi, Antonio Rossi, L. Ghilardi, Paolo Graziano, C. Casartelli, Pamela Pizzutilo, Diego Cortinovis, Silvia Novello, Rita Chiari, P. Rizzo, and Emilio Bria
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Anaplastic lymphoma kinase ,Retrospective cohort study ,business - Published
- 2018
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39. Functions and regulation of the MRX complex at DNA double-strand breaks
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Diego Bonetti, Matteo Villa, Corinne Cassani, Maria Pia Longhese, Elisa Gobbini, Gobbini, E, Cassani, C, Villa, M, Bonetti, D, and Longhese, M
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0301 basic medicine ,double-strand break ,Applied Microbiology ,Saccharomyces cerevisiae ,BIO/18 - GENETICA ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Applied Microbiology and Biotechnology ,Microbiology ,MRX ,Resection ,03 medical and health sciences ,chemistry.chemical_compound ,Nuclease ,Rif2 ,Virology ,Genetics ,resection ,Molecular Biology ,lcsh:QH301-705.5 ,Sae2 ,Double strand ,Kinase ,fungi ,Tel1 ,Cell Biology ,biology.organism_classification ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,MRX complex ,chemistry ,lcsh:Biology (General) ,Parasitology ,nucleases ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,DNA ,Function (biology) - Abstract
DNA double-strand breaks (DSBs) pose a serious threat to genome stability and cell survival. Cells possess mechanisms that recognize DSBs and promote their repair through either homologous recombination (HR) or non-homologous end joining (NHEJ). The evolutionarily conserved Mre11-Rad50-Xrs2 (MRX) complex plays a central role in the cellular response to DSBs, as it is implicated in controlling end resection and in maintaining the DSB ends tethered to each other. Furthermore, it is responsible for DSB signaling by activating the checkpoint kinase Tel1 that, in turn, supports MRX function in a positive feedback loop. The present review focuses mainly on recent works in the budding yeast Saccharomyces cerevisiae to highlight structure and regulation of MRX as well as its interplays with Tel1.
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- 2016
40. Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity
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Matteo Villa, Michela Clerici, Elisa Gobbini, Luca Menin, Maria Pia Longhese, Marco Gnugnoli, Gobbini, E, Villa, M, Gnugnoli, M, Menin, L, Clerici, M, and Longhese, M
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double-strand break ,Genome instability ,Cancer Research ,Cell cycle checkpoint ,Saccharomyces cerevisiae Proteins ,lcsh:QH426-470 ,DNA damage ,BIO/18 - GENETICA ,Cell Cycle Proteins ,Saccharomyces cerevisiae ,yeast ,Biology ,Protein Serine-Threonine Kinases ,Genomic Instability ,checkpoint ,Genetics ,Hypersensitivity ,DNA Breaks, Double-Stranded ,Phosphorylation ,Homologous Recombination ,Sae2 ,Molecular Biology ,Checkpoint Kinase 2 ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,RecQ Helicases ,fungi ,Cell Cycle ,DNA Helicases ,Intracellular Signaling Peptides and Proteins ,G2-M DNA damage checkpoint ,Cell cycle ,Endonucleases ,lcsh:Genetics ,MRX complex ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Homologous recombination ,Research Article ,DNA Damage - Abstract
The MRX complex together with Sae2 initiates resection of DNA double-strand breaks (DSBs) to generate single-stranded DNA (ssDNA) that triggers homologous recombination. The absence of Sae2 not only impairs DSB resection, but also causes prolonged MRX binding at the DSBs that leads to persistent Tel1- and Rad53-dependent DNA damage checkpoint activation and cell cycle arrest. Whether this enhanced checkpoint signaling contributes to the DNA damage sensitivity and/or the resection defect of sae2Δ cells is not known. By performing a genetic screen, we identify rad53 and tel1 mutant alleles that suppress both the DNA damage hypersensitivity and the resection defect of sae2Δ cells through an Sgs1-Dna2-dependent mechanism. These suppression events do not involve escaping the checkpoint-mediated cell cycle arrest. Rather, defective Rad53 or Tel1 signaling bypasses Sae2 function at DSBs by decreasing the amount of Rad9 bound at DSBs. As a consequence, reduced Rad9 association to DNA ends relieves inhibition of Sgs1-Dna2 activity, which can then compensate for the lack of Sae2 in DSB resection and DNA damage resistance. We propose that persistent Tel1 and Rad53 checkpoint signaling in cells lacking Sae2 increases the association of Rad9 at DSBs, which in turn inhibits DSB resection by limiting the activity of the Sgs1-Dna2 resection machinery., Author Summary Genome instability is one of the most pervasive characteristics of cancer cells and can be due to DNA repair defects and failure to arrest the cell cycle. Among the many types of DNA damage, the DNA double strand break (DSB) is one of the most severe, because it can cause mutations and chromosomal rearrangements. Generation of DSBs triggers a highly conserved mechanism, known as DNA damage checkpoint, which arrests the cell cycle until DSBs are repaired. DSBs can be repaired by homologous recombination, which requires the DSB ends to be nucleolytically processed (resected) to generate single-stranded DNA. In Saccharomyces cerevisiae, DSB resection is initiated by the MRX complex together with Sae2, whereas more extensive resection is catalyzed by both Exo1 and Dna2-Sgs1. The absence of Sae2 not only impairs DSB resection, but also leads to the hyperactivation of the checkpoint proteins Tel1/ATM and Rad53, leading to persistent cell cycle arrest. In this manuscript we show that persistent Tel1 and Rad53 signaling activities in sae2Δ cells cause DNA damage hypersensitivity and defective DSB resection by increasing the amount of Rad9 bound at the DSBs, which in turn inhibits the Sgs1-Dna2 resection machinery. As ATM inhibition has been proposed as a strategy for cancer treatment, the finding that defective Tel1 signaling activity restores DNA damage resistance in sae2Δ cells might have implications in cancer therapies that use ATM inhibitors for synthetic lethal approaches that are devised to kill tumor cells with defective DSB repair.
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- 2015
41. P2.03b-063 Molecular Profiling in Advanced Non-Small-Cell Lung Cancer: Preliminary Data of an Italian Observational Prospective Study
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Vieri Scotti, Angelo Delmonte, Giulio Rossi, Saverio Cinieri, Vanesa Gregorc, Massimo Di Maio, Alice Lunghi, Giulia Pasello, Paola Bordi, Lucio Buffoni, Olga Martelli, Ferdinando Riccardi, Anna Ceribelli, Tindara Franchina, Antonio Rossi, Maria Rita Migliorino, Diego Cortinovis, Silvia Novello, Evaristo Maiello, Salvatore Pisconti, Concetta Sergi, Elisa Gobbini, Paolo Graziano, Emilio Bria, and Domenico Galetta
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Pulmonary and Respiratory Medicine ,Oncology ,business.industry ,Medicine ,Profiling (information science) ,Observational study ,Non small cell ,business ,Bioinformatics ,Lung cancer ,medicine.disease ,Prospective cohort study - Published
- 2017
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42. DNA amount comparison between cytologic and histologic samples for epithelial growth factor receptor (EGFR) testing in non-small-cell lung cancer (NSCLC) patients: a single institution experience
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M. Giaj Levra, Lucio Buffoni, Silvia Novello, E. De Luca, Enrica Capelletto, Luisella Righi, Elisa Gobbini, M. Gianetta, and Maria Lucia Reale
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Oncology ,medicine.medical_specialty ,Growth factor receptor ,business.industry ,Internal medicine ,Cytology ,Medicine ,non-small cell lung cancer (NSCLC) ,Hematology ,Single institution ,business ,medicine.disease - Published
- 2017
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43. Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks
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Daniele Cesena, Maria Pia Longhese, Elisa Gobbini, Alessandro Galbiati, Arianna Lockhart, Gobbini, E, Cesena, D, Galbiati, A, Lockhart, A, and Longhese, M
- Subjects
Genome instability ,Saccharomyces cerevisiae Proteins ,DNA Repair ,DNA repair ,DNA damage ,MRN/MRX ,Cell Cycle Proteins ,BIO/18 - GENETICA ,Ataxia Telangiectasia Mutated Proteins ,Saccharomyces cerevisiae ,Biology ,Protein Serine-Threonine Kinases ,Biochemistry ,chemistry.chemical_compound ,Humans ,ATM/Tel1 ,DNA Breaks, Double-Stranded ,CHEK1 ,Molecular Biology ,Genetics ,Checkpoint ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Cell Cycle Checkpoints ,Cell cycle ,G2-M DNA damage checkpoint ,Resection ,ATR/Mec1 ,Cell biology ,Checkpoint Kinase 2 ,DNA Repair Enzymes ,MRN complex ,chemistry ,DNA double-strand break ,Schizosaccharomyces pombe Proteins ,biological phenomena, cell phenomena, and immunity ,DNA ,Signal Transduction - Abstract
DNA double-strand breaks (DSBs) are highly hazardous for genome integrity because they have the potential to cause mutations, chromosomal rearrangements and genomic instability. The cellular response to DSBs is orchestrated by signal transduction pathways, known as DNA damage checkpoints, which are conserved from yeasts to humans. These pathways can sense DNA damage and transduce this information to specific cellular targets, which in turn regulate cell cycle transitions and DNA repair. The mammalian protein kinases ATM and ATR, as well as their budding yeast corresponding orthologs Tel1 and Mec1, act as master regulators of the checkpoint response to DSBs. Here, we review the early steps of DSB processing and the role of DNA-end structures in activating ATM/Tel1 and ATR/Mec1 in an orderly and reciprocal manner.
- Published
- 2013
44. Molecular profiling in advanced non-small-cell lung cancer: preliminary data of the Italian observational prospective study
- Author
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Anna Ceribelli, G.B. Rossi, Tindara Franchina, Elisa Gobbini, Maria Rita Migliorino, Diego Cortinovis, F. Riccardi, Silvia Novello, M. Tiseo, Lucio Buffoni, Angelo Delmonte, Vieri Scotti, M. Di Maio, Evaristo Maiello, Aroldo Rossi, V. Grecorc, Salvatore Pisconti, Emilio Bria, Domenico Galetta, and Paolo Graziano
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Oncology ,medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Internal medicine ,medicine ,Profiling (information science) ,Observational study ,Non small cell ,Lung cancer ,Prospective cohort study ,business - Published
- 2016
- Full Text
- View/download PDF
45. Intercalated chemotherapy and epidermal growth factor receptor inhibitors for patients with advanced non-small-cell lung cancer: a systematic review and meta-analysis
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Emmanuele De Luca, Anna La Salvia, Antonio Rossi, Elisa Gobbini, Domenico Galetta, Massimo Di Maio, and Silvia Novello
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Epidermal Growth Factor Receptor Inhibitors ,Afatinib ,medicine.medical_treatment ,Antineoplastic Agents ,Pharmacology ,NSCLC ,law.invention ,Erlotinib ,Gefitinib ,Mutation ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Epidermal growth factor ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Chemotherapy ,business.industry ,Hazard ratio ,Hematology ,Prognosis ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Meta-analysis ,Non small cell ,business ,medicine.drug - Abstract
Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non–small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G 1 cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P P P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P P EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P P EGFR mutation-positive tumors included.
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- 2016
- Full Text
- View/download PDF
46. G(1)/S and G(2)/M cyclin-dependent kinase activities commit cells to death in the absence of the S-phase checkpoint
- Author
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Maria Pia Longhese, Veronica Baldo, Giovanna Lucchini, Elisa Gobbini, Nicola Manfrini, Camilla Trovesi, Manfrini, N, Gobbini, E, Baldo, V, Trovesi, C, Lucchini, G, and Longhese, M
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DNA Replication ,Cell cycle checkpoint ,Saccharomyces cerevisiae Proteins ,Genes, Fungal ,Cell Cycle Proteins ,Saccharomyces cerevisiae ,Biology ,Protein Serine-Threonine Kinases ,Spindle elongation ,Cyclin-dependent kinase ,CDC2 Protein Kinase ,Hydroxyurea ,CDK1, Checkpoint, Mec1, Rad53 ,Molecular Biology ,Mitosis ,Cyclin-dependent kinase 1 ,DNA replication ,Intracellular Signaling Peptides and Proteins ,Cell Biology ,Articles ,G2-M DNA damage checkpoint ,G1 Phase Cell Cycle Checkpoints ,Cell biology ,G2 Phase Cell Cycle Checkpoints ,Checkpoint Kinase 2 ,Mutation ,S Phase Cell Cycle Checkpoints ,biology.protein - Abstract
The Mec1 and Rad53 protein kinases are essential for budding yeast cell viability and are also required to activate the S-phase checkpoint, which supports DNA replication under stress conditions. Whether these two functions are related to each other remains to be determined, and the nature of the replication stress-dependent lethality of mec1 and rad53 mutants is still unclear. We show here that a decrease in cyclin-dependent kinase 1 (Cdk1) activity alleviates the lethal effects of mec1 and rad53 mutations both in the absence and in the presence of replication stress, indicating that the execution of a certain Cdk1-mediated event(s) is detrimental in the absence of Mec1 and Rad53. This lethality involves Cdk1 functions in both G(1) and mitosis. In fact, delaying either the G(1)/S transition or spindle elongation in mec1 and rad53 mutants allows their survival both after exposure to hydroxyurea and under unperturbed conditions. Altogether, our studies indicate that inappropriate entry into S phase and segregation of incompletely replicated chromosomes contribute to cell death when the S-phase checkpoint is not functional. Moreover, these findings suggest that the essential function of Mec1 and Rad53 is not necessarily separated from the function of these kinases in supporting DNA synthesis under stress conditions.
- Published
- 2012
47. Telomere uncapping at the crossroad between cell cycle arrest and carcinogenesis
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Camilla Trovesi, Maria Pia Longhese, Corinne Cassani, and Elisa Gobbini
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Genome instability ,double-strand breaks ,telomere ,Cancer Research ,Cell cycle checkpoint ,DNA repair ,Cell growth ,Telomere Capping ,Review ,G2-M DNA damage checkpoint ,Biology ,genomic stability ,Molecular biology ,Telomere ,Cell biology ,checkpoint ,cancer ,Molecular Medicine ,Uncapping - Abstract
Telomeres are nucleoprotein complexes that protect the natural ends of chromosomes from fusion and degradation and prevent them eliciting a checkpoint response. This protective function, which is called telomere capping, is largely mediated by telomere-binding proteins that suppress checkpoint activation and DNA repair activities. Telomere dysfunction through progressive shortening or removal of capping proteins leads to a checkpoint-mediated block of cell proliferation, which acts as a cancer-suppressor mechanism. However, genetic alterations that inactivate the checkpoint can lead to further telomere erosion and increased genomic instability that, coupled with the activation of mechanisms to restabilize telomeres, can drive the oncogenic process.
- Published
- 2014
- Full Text
- View/download PDF
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