Background: Despite recent advances in the treatment of multiple myeloma (MM) patients, cure remains rare. MM is in an era of intense clinical research and the molecular abnormalities landscape of ...refractory and relapsed (R/R) patients is of major interest for drug development. Furthermore, innovative molecular-oriented treatments for these R/R patients could be oriented by mutational characterization of myeloma plasma cells (PC). At relapse but also for clonal minimal residual disease monitoring on therapy, bone marrow aspiration is an invasive procedure that can give limited information since PC infiltration is heterogeneous and can be modest. Mutational profiling on circulating cell-free tumoral DNA (ctDNA) could be a simple and appropriate alternative.
Method: We compared molecular landscape in myeloma PC versus in ctDNA in a cohort of 45 R/R MM patients screened at Gustave Roussy for a salvage therapy, most of them for a Phase I trial in the DITEP department, with a median age at time of molecular analysis of 69 years. All patients had received ≥ 1 prior lines of myeloma therapy (median: 2, range: 1-8), 33/45 (73%) had previously undergone autologous stem cell transplant and 14/45 (31%) had received prior daratumumab; 6/45 (13%) were double-refractory (to at least a proteasome inhibitor (PI) and an immunomodulatory imide drug (IMiD), 4/45 (9%) were triple-refractory and 1/45 (2%) was penta-refractory. Four patients (9%) had prior daratumumab and were also double-refractory. Paired samples, as well as normal sorted CD3 + T cells were sequenced using an Ion Torrent custom panel covering 30 myeloma-related genes previously reported as the most frequent mutated ones. The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol.
Results: One hundred and two variants were found in magnetic-sorted CD138 + myeloma PC, and 99 variants were detected in ctDNA; more than half of the variants detected in myeloma PC were also found in ctDNA (55/102, 54%). Variant allelic frequencies (VAF) in PC and in ctDNA were significantly correlated (p<0.001). Mean VAF was 25% in myeloma PC (median 19%, range: 0.40-99%) and 5.4% in ctDNA (median 0.33%, range: 0-50%) considering the 102 mutations found in myeloma PC. KRAS, NRAS, FAM46C, DIS3 and TP53 were the most frequently mutated genes (i.e. >10% of R/R MM). Considering these five key driver genes, the kappa coefficient of concordance per gene was medium/good between both samples, as defined by the Landis-Koch scale. The mean and median sensitivity of ctDNA detection per gene was 55% and 58% respectively (range: 38-67), and specificity 94% and 97% (range: 80-100); positive predictive value of TP53 mutations detection was poor as theses mutations were more frequently detected in ctDNA (12/45, 27%) than in myeloma PC (6/45, 13%). At the patient level, the similarity between myeloma PC and ctDNA (level defined as the ratio between SNV number in PC and SNV number in ctDNA) was greater than a threshold of 80% in 20/39 (51%) cases (median level: 100%). Importantly, key driver gene mutations were reported in ctDNA for 13/28 (48%) patients without cytological evidence of infiltrated plasmocytosis (less than 10% PC) in the bone marrow aspiration.
Conclusions: ctDNA profiling may complete molecular description of R/R MM patients thanks to a less-invasive procedure, allowing to fully characterize mutational profile prior to molecular-oriented treatment decision. ctDNA can give information on the clonal architecture in patients without bone marrow infiltration even after CD138 + cells magnetic-sorted isolation.
Michot: BMS: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Lazarovici: Mundipharma: Other: Travel grant. Ribrag: Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; GSK: Research Funding; Epizyme: Honoraria, Research Funding; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background. Diffuse large B cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma. Despite therapeutic advances, 40% of the patients (pts) and especially pts older than 65 years old ...(y/o), will experience a relapsed or refractory (R/R) disease. Novel therapies as well as predictive biomarkers are required for these patients with a poor prognosis after standard salvage regimens. We aimed at establishing whether tumor molecular characterization by a customized target panel in pts with R/R DLBLC prior to enrollment in a phase I clinical trials might impact therapeutic decision making and outcome prediction.
Methods. Paired targeted next generation sequencing for all consecutive pts with R/R DLBCL from germline sample and fresh tumor biopsy were performed at the time of enrollment in phase I clinical trials within the early phase clinical department. Tumor and germline samples of enrolled patients were sequenced using Ion Torrent technology on an in-house customized panel of 44 genes. Molecular and cluster mapping of recurrent molecular abnormalities was determined by integrated completed likelihood (ICL) in patients with relapsed diffuse large B-cell lymphoma. Predictive and prognostic impact of molecular profile was assessed on overall survival (OS).
Results. Between 2013 and 2020, 89 pts with R/R DLBCL were included in the study. At time of inclusion, mean age was 62 (range 23-83) y/o, 50 pts (56%) were male, median prior lines of systemic treatment was 2 (range 1-9). Age adjusted international prognostic index (aaIPI) score was 0-1 in 42 pts (47%) and 2-3 in 47 pts (53%). Among the 82 cases with a cell of origin (COO) status assessed by immunohistochemistry, 55 (67%) pts had a germinal center (GC) and 27 pts (33%) a non-GC. The sequencing panel was informative in 86 pts (97%) and 3 pts (3%) had no variants identified. The most recurrently altered genes by mutations (m) were TP53m (n=38; 43%), CREBBPm (n=29; 33%), KMT2Dm (n=24; 27%), PIM1m (n=23; 26%) and BCL2m (n=20; 22%). Mutual exclusivity and co-occurrence analysis underlined that KMT2Dm were fully exclusive from MEF2Bm (p<0.0001); and TNFRSF14m highly significantly co-occurred with BCL2m (p=0.0001). From an unsupervised ICL clustering (based on a distance matrix derived from the presence or absence of variants within the 44 genes), 67/86 pts (78%) with one or more somatic variant could be classified into four distinct genetic groups: group M/K (n=21 patients 24% enriched in MYCm, EZH2m and KMT2Dm; group S (n=18 patients 20%, enriched in SOCS1m, B2Mm, STAT6m and PIM1m), group B (n=17 patients 19%, enriched in BCL2m, GNA13m, TNFSRF14m and MEF2Bm) and group M/C (n=11 patients 12%, enriched in MYD88m and CD79Bm) (figure 1). Within B and M/K groups, the vast majority had a GCB COO status (n=17/17 100% in the B group and n=19/21 90% in the M/K group), whereas within M/C and S groups the COO status was evenly distributed (n=5 GC versus vs n=5 non-GC in M/C group; n=7 GC vs n=8 non-GC in S group). Based on their distinct patterns these four genetic groups could serve as a basis for molecular driven targeted therapeutic approaches; such as epigenetics modifiers for M/K group, JAK-STAT pathway inhibitors for S group, BCL2 and apoptosis inhibitors for B group and BTK downstream inhibitors for M/C group. As an exploratory analysis, univariate prognostic analysis for OS was performed. A shorter OS was associated with ECOG performance status ≥2 vs 0-1 (p<0.0001) and Ann Arbor stage III-IV vs I-II (p=0.0023); while the other clinical characteristics were not found significantly associated (including age ≥ 60 y/o vs <60 y/o p=0.2741 and LDH elevated vs non-elevated p=0.1883). Among the most recurrently altered genes, a shorter OS was associated with GNA13m (p=0.0009), CARD11m (p=0.0147), CDKN2Am (p=0.0192) and MYCm (p=0.0220); whereas no significant association was found between the four distinct genetic patient’s groups (p=0.7301).
Conclusion. A molecular tumor characterization of patients with R/R DLBCL emphasizes high incidence of TP53 and epigenetic modifying oncogenes CREBBP and KMT2D mutations. Four distinct genetic clusters were identified that could serve as the basis for a molecular-matched therapeutic approach.
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Michot:Medimmune: Research Funding; Lytix Biopharma: Research Funding; Lysarc: Research Funding; Janssen: Other, Research Funding; Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Agios: Research Funding; AZD: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Xencor: Research Funding; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Other; Sanofi: Research Funding; Roche: Research Funding; Argen-x: Research Funding; Abbvie: Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Astex: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Lilly: Research Funding; Mundi Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Research Funding; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Debiopharm: Research Funding; Daiichi Sankyo: Research Funding; Forma: Research Funding; Genentech: Research Funding; Kyowa: Research Funding. Varga:Astra Zeneca: Current Employment. Ribrag:Roche/Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Nanostring: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Immune Design: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Institut Gustave Roussy: Current Employment; Pharmamar: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees; argenX: Current equity holder in publicly-traded company, Research Funding; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Early drug development is associated with a high rate of failure in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBLC), partly due to genomic heterogeneity. ...Precision medicine aims at identifying patients with cancer who are likely to respond to targeted therapies. Here we assessed the clinical impact of characterizing actionable and molecular targets and matching targeted therapy in pts with R/R DLBCL prior enrollment in early phase clinical trials (epCT).
Methods: Pts with R/R DLBCL enrolled in epCT, provided paired samples including germline and fresh tumor tissue sample. Paired samples were analyzed by targeted next generation sequencing (NGS) using a customized panel of 44 genes (Ion Torrent). Clinical actionability of genomic alterations and orientation to targeted therapy were prospectively assessed at the Hematological Tumor Board from our Institution according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) tiers (ESCAT scale; J. Mateo, Annals of Oncology, 20181). Pts were classified as molecularly matched (MM) i.e. treated based on the presence of an ESCAT actionable molecular abnormality, or non-molecularly matched (no-MM). Tumor and clinical characteristics and outcome of pts were collected.
Results: From 2013 to 2020, 90 pts with R/R DLBCL screened for early clinical trial had tumor & germline samples sequenced by NGS. The mean age was 62 years old (range, 23-83) and median prior lines of systemic therapy was 2 (range 1-9). Sixteen (18%) pts were enrolled in epCT and treated with MO drugs, 43 pts (48%) were enrolled in epCT and treated with no-MM drugs, and 31 (34%) pts were not enrolled in epCT. The main clinical characteristics of the pts were similar in both MM and no-MM groups (table 1). Based on ESCAT scale, targeted therapies of the 16 pts MM were distributed as “investigational-level” tier II in 6 pts (3 pts EZH2 mutant m treated with EZH2 inhibitors; 3 patients with a CD79Bm treated with BTK inhibitors); “hypothetical-level” tier III in 1 pt BRAFm treated with a BRAF inhibitor; and “hypothetical-level” tier IV in 9 pts (6 pts MYD88m treated with cereblon modulator drugs; 2 pts with BCL7Am/ARID1Am treated with investigational epigenetic modifier drugs; 1 pt with MYCm treated with a PI3K inhibitor). Median progression-free survival in MM and no-MM pts, were 3.3 and 1.7 months, respectively (p=0.0092; HR=0.47 CI95:0.27-0.83). Median overall survival in MM and no-MM pts were 20.0 and 6.7 months, respectively (p=0.0238; HR=0.49 CI95: 0.26-0.91) (figure 1).
Conclusions: Molecular orientation before inclusion in early phase clinical trials was associated with better outcomes in patients with R/R DLBCL. A molecular tumor profile could be useful to manage patients with R/R DLBCL with precision medicine helping to identify patients likely to respond to targeted therapies.
Reference.
1- Mateo J, Chakravarty D, Dienstmann R et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Annals of Oncology 2018; 29(9):1895-1902.
Table 1.Patient's characteristics at time of R/R DLBCL relapse and tumor sample in molecularly matched patients (MM group) and non-molecularly matched patients (no-MM group). Data presented are n (%) unless otherwise stated.
MM= Molecularly matched. no-MM= Non-molecularly matched. R/R DLBCL= relapsed or refractory diffuse large B-cell lymphoma. y.o. = years old. mo.= months. ECOG PS= Eastern Cooperative Oncology Group performance status. NHL=non-Hodgkin lymphoma. ASCT= Autostem cell transplantation. IHC= Immunohistochemistry. COO= Cell of origin. GC= Germinal center. ABC= Activated B-cell. NA= Not available. LDH= Lactate deshydrogenase.
*the p-value indicates the comparison between the proportions of the groups from a contingency table, and was calculated by the exact Fisher test. All tests were non-parametric. The p values were calculated by two-tailed and a 95% confidence interval was used, with values less than 0.005 considered being significantly different.
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Michot:Argen-x: Research Funding; Eos: Research Funding; Exelixis: Research Funding; Amgen: Research Funding; Astex: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Research Funding; Daiichi Sankyo: Research Funding; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Lysarc: Research Funding; Lilly: Research Funding; Kyowa: Research Funding; Genentech: Research Funding; Forma: Research Funding; Agios: Research Funding; AZD: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundi Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Other; Xencor: Research Funding; Sanofi: Research Funding; Roche: Research Funding; Medimmune: Research Funding; Lytix Biopharma: Research Funding; Janssen: Other, Research Funding; Debiopharm: Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Abbvie: Research Funding. Varga:Astra Zeneca: Current Employment. Ribrag:argenX: Current equity holder in publicly-traded company, Research Funding; Roche/Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Institut Gustave Roussy: Current Employment; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Eisai: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Servier: Consultancy, Honoraria; AstraZeneca: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Nanostring: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Immune Design: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel Expenses; Infinity: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) often do poorly with conventional salvage regimens of chemotherapy. Next-generation sequencing (NGS) panels ...can rapidly identify recurrent molecular abnormalities, thus helping to orient patients (pts) in appropriate targeted therapies or clinical trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with a better outcome.
Methods: From 2013 to 2018, all pts with r/r DLBCL having molecular portrait of tumor before enrollment in early clinical trials (eaCTs) for r/r DLBCL were analyzed for clinical and histomolecular characteristics, tumor response, progression-free survival (PFS) duration of response and overall survival. The objective were to evaluate the feasibility and potential benefit of using tumor genotyping for guiding enrollment in eaCTs. Molecular screening methods included immunohistochemistry, PCR-based assays and next-generation sequencing. All pts gave their written consent for the study.
Results: Sixty-two pts with r/r DLBCL had tumor molecular portraits. At the time of tumor molecular portrait, the median age was 69 years (range 26-77), median of previous line of therapies was 2 (range 1-9) and 14 pts (23%) had prior received auto stem-cell transplant. Fifteen out of the 62 pts (24%) were molecularly oriented (MO) in eaCTs. Identification of potentially actionable targets was found in 30/62 (48%) of pts, of whom 15/30 (50%) received a molecularly-informed therapy. Beyond molecular portrait, fifty pts were enrolled in eaCTs (15 pts were MO and 35 were non-MO oriented) and 12 pts were not enrolled in eaCTs. The MO-oriented group included the following therapeutic targets: CD79A/B or MYD88 (n=10 pts), EZH2 or ARIDI1A (n=3 pts), MYC (n=1 pt) and BRAF (n=1 pt). The overall responses rate was 60% (6 PR and 3 CR) in MO group versus 23% (5 PR and 2 CR) in non-MO group (p= 0.01). The median of PFS in MO and non-MO groups were 2.2 months and 1.9 months, respectively (p=0.23; HR=0.69 CI95:0.38-1.26). The median duration of response in MO and non-MO groups were 10.9 and 9.3 months, respectively (p=0.78; HR=0.76 CI95: 0.26-2.18. The mean PF2/PF1 ratio in MO and non-MO groups were 2.34 CI95: 0.27-4.41 and 1.67 CI:0.53-2.81, respectively (p=0.093; HR=0.61 CI95: 0.33-1.14. The median overall survival in MO and non-MO groups were 8.9 and 7.7 months, respectively (p=0.34; HR=0.69 CI95: 0.33-1.47).
Conclusions: Molecularly oriented treatments of recurrent diffuse large B-cell lymphoma demonstrates higher responses rates. A subset of patients with recurrent or refractory diffuse large B-cell lymphoma may benefit from incorporation of tumor genotyping to guide their enrollment in clinical trials. Accelerating the use of prospective genomics tumor molecular portraits may increase the chances for a precision medicine for recurrent diffuse large B-cell lymphoma.
Soria:Medimmune: Employment. Ribrag:BMS: Consultancy, Honoraria, Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria; NanoString Technologies: Consultancy, Honoraria; argenX: Research Funding; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; pharmamar: Other: travel; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Amgen: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lake Dziani Dzaha is a thalassohaline tropical crater lake located on the "Petite Terre" Island of Mayotte (Comoros archipelago, Western Indian Ocean). Stromatolites are actively growing in the ...shallow waters of the lake shores. These stromatolites are mainly composed of aragonite with lesser proportions of hydromagnesite, calcite, dolomite, and phyllosilicates. They are morphologically and texturally diverse ranging from tabular covered by a cauliflower-like crust to columnar ones with a smooth surface. High-throughput sequencing of bacterial and archaeal 16S rRNA genes combined with confocal laser scanning microscopy (CLSM) analysis revealed that the microbial composition of the mats associated with the stromatolites was clearly distinct from that of the
-dominated lake water. Unicellular-colonial Cyanobacteria belonging to the
genus of the Pleurocapsales order were detected in the cauliflower crust mats, whereas filamentous Cyanobacteria belonging to the
genus were found in the smooth surface mats. Observations using CLSM, scanning electron microscopy (SEM) and Raman spectroscopy indicated that the cauliflower texture consists of laminations of aragonite, magnesium-silicate phase and hydromagnesite. The associated microbial mat, as confirmed by laser microdissection and whole-genome amplification (WGA), is composed of Pleurocapsales coated by abundant filamentous and coccoid Alphaproteobacteria. These phototrophic Alphaproteobacteria promote the precipitation of aragonite in which they become incrusted. In contrast, the Pleurocapsales are not calcifying but instead accumulate silicon and magnesium in their sheaths, which may be responsible for the formation of the Mg-silicate phase found in the cauliflower crust. We therefore propose that Pleurocapsales and Alphaproteobacteria are involved in the formation of two distinct mineral phases present in the cauliflower texture: Mg-silicate and aragonite, respectively. These results point out the role of phototrophic Alphaproteobacteria in the formation of stromatolites, which may open new perspective for the analysis of the fossil record.
Circulating endothelial progenitor cells (cEPC) are capable of homing to neovascularisation sites, in which they proliferate and differentiate into endothelial cells. Transplantation of cEPC-derived ...cells, in particular those isolated from umbilical cord blood (UCB), has emerged as a promising approach in the treatment of cardio-vascular diseases. After in vivo transplantation, these cells may be exposed to local or systemic inflammation or pathogens, of which they are a common target. Because Toll-like receptors (TLR) are critical in detecting pathogens and in initiating inflammatory responses, we hypothesized that TLR may govern UCB cEPC-derived cells function. While these cells expressed almost all TLR, we found that only TLR3 dramatically impaired cell properties. TLR3 activation inhibited cell proliferation, modified cell cycle entry, impaired the in vitro angiogenic properties and induced pro-inflammatory cytokines production. The anti-angiogenic effect of TLR3 activation was confirmed in vivo in a hind-limb ischemic mice model. Moreover, TLR3 activation consistently leads to an upregulation of miR-29b, -146a and -155 and to a deregulation of cytoskeleton and cell cycle regulator. Hence, TLR3 activation is likely to be a key regulator of cEPC-derived cells properties.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Cachexia is a complex syndrome defined by weight loss due to an ongoing loss of skeletal muscle mass with or without loss of body fat. It is often associated with anorexia. Numerous ...results from experimental studies suggest that blockade of the melanocortin-4 receptor (MC4R) could be an effective treatment for anorexia and cachexia. In a previous study, we reported the basic pharmacological properties of a blocking anti-MC4R mAb 1E8a and its scFv derivative in vitro and in vivo.
Methods
In the present study, we further characterized the mode of action of the 1E8a scFv, evaluated its pharmacokinetic properties in mice, and assessed its therapeutic potential in a lipopolysaccharide (LPS)-induced cachexia model in rats.
Results
In vitro, scFv enhanced the efficacy of the endogenous inverse agonist Agouti-related protein. After intravenous (i.v.) administration in mice, the scFv penetrated the blood–brain barrier (BBB) and reached its central sites of action: the scFv brain–serum concentration ratios increased up to 15-fold which suggests an active uptake into brain tissue. In telemetry experiments, i.v. administration of the scFv in rats was well tolerated and only induced slight cardiovascular effects consistent with MC4R blockade, i.e., a small decrease in mean arterial pressure and heart rate. In the model of LPS-induced anorexia, i.v. administration of scFv 1E8a prevented anorexia and loss of body weight. Moreover, it stimulated a myogenic response which may contribute to the preservation of muscle mass in cachexia.
Conclusion
The pharmacological profile of scFv 1E8a suggests its potential value in the treatment of cachexia or anorexia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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