A weed control source unit

Call number: LD2668 .R4 1968 E4

Updated Safety And Efficacy Data In The Phase 1 Trial Of Patients With Mantle Cell Lymphoma (Mcl) Treated With Bruton Tyrosine Kinase (Btk) Inhibitor Zanubrutinib (Bgb‐3111)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149513/1/hon55_2630.pd

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

Autologous Stem Cell Transplant is Feasible in Very Elderly Patients with Lymphoma and Limited Comorbidity

In patients with recurrent Hodgkin or non-Hodgkin\u27s lymphoma, autologous stem cell transplantation (ASCT) can offer potential for cure or long-term remission. Because of potential toxicity, elderly patients are usually not considered candidates, but data regarding tolerability and efficacy in this group are lacking. The transplant database at Weill Cornell Medical College was reviewed to identify patients with lymphoma undergoing ASCT at age 69 or greater. Clinical data and comorbidities were correlated with outcome. Twenty-one patients were identified. Sixteen of 19 evaluable patients (76%) achieved complete remission following ASCT, while 2 patients died before response assessment. Median progression-free survival following ASCT was 8 months and median overall survival was 18 months. Age was not predictive of overall survival, but patients 75 and older had inferior progression-free survival compared to younger patients. High-risk status by hematopoietic stem cell transplant comorbidity index (HCT-CI) was associated with short overall survival and high transplant-related mortality. ASCT is feasible and of potential benefit in selected elderly lymphoma patients. Consideration of comorbidities, rather than age alone, may allow selection of patients likely to tolerate and benefit from ASCT

Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets

<div><p>Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway <i>i</i>.<i>e</i>., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times <i>vs</i>. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.</p></div

Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

Dose‐dependent proteomic analysis of glioblastoma cancer stem cells upon treatment with γ‐secretase inhibitor

Notch signaling has been demonstrated to have a central role in glioblastoma (GBM) cancer stem cells (CSCs) and we have demonstrated recently that Notch pathway blockade by γ‐secretase inhibitor (GSI) depletes GBM CSCs and prevents tumor propagation both in vitro and in vivo. In order to understand the proteome alterations involved in this transformation, a dose‐dependent quantitative mass spectrometry (MS)‐based proteomic study has been performed based on the global proteome profiling and a target verification phase where both Immunoassay and a multiple reaction monitoring (MRM) assay are employed. The selection of putative protein candidates for confirmation poses a challenge due to the large number of identifications from the discovery phase. A multilevel filtering strategy together with literature mining is adopted to transmit the most confident candidates along the pipeline. Our results indicate that treating GBM CSCs with GSI induces a phenotype transformation towards non‐tumorigenic cells with decreased proliferation and increased differentiation, as well as elevated apoptosis. Suppressed glucose metabolism and attenuated NFR2‐mediated oxidative stress response are also suggested from our data, possibly due to their crosstalk with Notch Signaling. Overall, this quantitative proteomic‐based dose‐dependent work complements our current understanding of the altered signaling events occurring upon the treatment of GSI in GBM CSCs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88055/1/4529_ftp.pd