7 research outputs found
Mesenchymal Stromal Cells Primed with Paclitaxel Provide a New Approach for Cancer Therapy
BACKGROUND: Mesenchymal stromal cells may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that exposure of mouse bone marrow derived stromal cells to Doxorubicin led them to acquire anti-proliferative potential towards co-cultured haematopoietic stem cells (HSCs). We thus hypothesized whether freshly isolated human bone marrow Mesenchymal stem cells (hMSCs) and mature murine stromal cells (SR4987 line) primed in vitro with anti-cancer drugs and then localized near cancer cells, could inhibit proliferation. METHODS AND PRINCIPAL FINDINGS: Paclitaxel (PTX) was used to prime culture of hMSCs and SR4987. Incorporation of PTX into hMSCs was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by PTX primed hMSCs (hMSCsPTX) was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti-angiogenic activity of hMSCsPTX and PTX primed SR4987(SR4987PTX), while anti-tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting hMSCsPTX and SR4987PTX with cancer cells in mice. Nevertheless, despite a loss of cells due to chemo-induced apoptosis, both hMSCs and SR4987 were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. PTX primed cells acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, hMSCsPTX and SR4987PTX co-injected with human cancer cells (DU145 and U87MG) and mouse melanoma cells (B16) in immunodeficient and in syngenic mice significantly delayed tumor takes and reduced tumor growth. CONCLUSIONS: These data demonstrate, for the first time, that without any genetic manipulation, mesenchymal stromal cells can uptake and subsequently slowly release PTX. This may lead to potential new tools to increase efficacy of cancer therapy
Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers
__Background__ Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association
with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects
of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine
whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth.
__Methods__ We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies
published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic
cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining
intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or
without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and populationbased studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations
and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies
not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from
groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and
Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a
random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and
perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from
study authors for all types of study (as no control group was required for the IPD analysis) to assess associations
between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is
registered with PROSPERO, number CRD42017069134.
__Findings__ We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis
(5557 intrahepatic cholestasis of pregnancy cases and 165136 controls), and 27 provided IPD (5269 intrahepatic
cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·91%) of 4936 intrahepatic cholestasis of pregnancy cases
and 519 (0·32%) of 163947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73–2·89]
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Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study
Introduction/Aims
Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti‐acetylcholine receptor antibody‐positive (AChR+) gMG previously treated with rituximab.
Methods
This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open‐label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE.
Results
Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous‐rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no‐previous‐rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous‐rituximab and no‐previous‐rituximab groups (least‐squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least‐squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post‐intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile.
Discussion
Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously