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Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several ...cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p < 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p < 0.001), including in those with IT (100% vs 72%, p < 0.001) and TT (88% vs 43%, p < 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.
Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) remain incurable using conventional chemotherapeutic approaches. Therefore it is important that new ...treatment strategies be developed. We have evaluated the efficacy of a number of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domain by linking DNA-affinic molecules to N-mustard pharmacophore via a urea, carbamate or hydrazinecarboxamide linker (Kapuriya et al. Bioorganic & Medicinal Chem. 19:471–485; 2011). One of these, the water-soluble ureidomustine BO-1055, was screened for toxicity against a panel of human lymphoma cell lines including MCL (JEKO-1, Z-138, HBL-2), DLBCL (OCILy10, OCILy19) and a spontaneous murine B-cell lymphoma. We also screened BO1055 against a panel of normal human cells including mesenchymal stromal cells (IC50 >10uM), bone marrow-derived endothelium (IC50 >10uM) lung basal epithelium, bronchial epithelium and myofibroblasts (IC50s >10uM) and purified cord blood CD34+ cells in suspension culture or colony-forming assay (for hematopoietic progenitor cells) (IC50 >10uM) and in cobblestone area-forming assay (for hematopoietic stem cells) (IC50 9.1uM). The mean IC50±SD (uM) in MCL cell lines was JEKO-1 (0.266±0.27), Z-138 (0.182±0.15), HBL2 (0.161±0.34), In DLBCL lines OCILy10 (0.117±0.21), OCILy19 (0.287±0.17) and murine B-cell lymphoma (0.463±0.39). Our results indicated that BO-1055 has a significant therapeutic window (50-100-fold) between its toxicity against human B-cell lymphomas compared to various normal human cell types. We evaluated BO-1055 cardiotoxicity in the HL-1 cardiomyocyte line and observed a 227-fold less cytotoxicity compared to Doxorubicin. Treatment with BO-1055 resulted in accumulation of cells in S-phase and up-regulation of proteins involved in DNA repair MRE11, p-P95/NBS1 (ser343), RAD50, p-ATR (ser428) while Bcl-6, an important B-cell lymphoma biomarker, was down-regulated. Xenograft experiments in NSG mice bearing JEKO-1 GFP/luciferase+ tumors treated with BO-1055 (30mg/kg) 3x/week showed complete tumor remission after 2 weeks of treatment as monitored by luciferase image. Our results suggest that BO-1055 has potent activity against B-cell lymphoma and present a strong rationale for its further therapeutic development as an alkylating agent due to his low toxicity against normal tissue and high toxicity against hematopoietic tumors.
No relevant conflicts of interest to declare.
Bloodstream infections (BSIs) occur in 20% to 45% of inpatient autologous and allogeneic hematopoietic cell transplant (HCT) patients. Daily bathing with the antiseptic chlorhexidine gluconate (CHG) ...has been shown to reduce the incidence of BSIs in critically ill patients, although very few studies include HCT patients or have evaluated the impact of compliance on effectiveness. We conducted a prospective cohort study with historical controls to assess the impact of CHG bathing on the rate of BSIs and gut microbiota composition among adults undergoing inpatient HCT at the Duke University Medical Center. We present 1 year of data without CHG bathing (2016) and 2 years of data when CHG was used on the HCT unit (2017 and 2018). Because not all patients adhered to CHG, patients were grouped into four categories by rate of daily CHG usage: high (>75%), medium (50% to 75%), low (1% to 49%), and none (0%). Among 192 patients, univariate trend analysis demonstrated that increased CHG usage was associated with decreased incidence of clinically significant BSI, defined as any BSI requiring treatment by the medical team (high, 8% BSI; medium, 15.2%; low, 15.6%; no CHG, 30.3%; P = .003), laboratory-confirmed BSI (LCBI; P = .03), central line-associated BSI (P = .04), and mucosal barrier injury LCBI (MBI-LCBI; P = .002). Multivariate analysis confirmed a significant effect of CHG bathing on clinically significant BSI (P = .023) and MBI-LCBI (P = .007), without consistently impacting gut microbial diversity. Benefits of CHG bathing were most pronounced with >75% daily usage, and there were no adverse effects attributable to CHG. Adherence to daily CHG bathing significantly decreases the rate of bloodstream infection following HCT.
Standard Reference Material 3280 Multivitamin/ Multielement Tablets was issued by the National Institute of Standards and Technology in 2009, and has certified and reference mass fraction values for ...13 vitamins, 26 elements, and two carotenoids. Elements were measured using two or more analytical methods at NIST with additional data contributed by collaborating laboratories. This reference material is expected to serve a dual purpose: to provide quality assurance in support of a database of dietary supplement products and to provide a means for analysts, dietary supplement manufacturers, and researchers to assess the appropriateness and validity of their analytical methods and the accuracy of their results.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND—Catecholamines increase heart rate by augmenting the cAMP-responsive hyperpolarization-activated cyclic nucleotide-gated channel 4 pacemaker current (If) and by promoting inward Na/Ca ...exchanger current (INCX) by a “Ca clock” mechanism in sinoatrial nodal cells (SANCs). The importance, identity, and function of signals that connect If and Ca clock mechanisms are uncertain and controversial, but the multifunctional Ca/calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to β-adrenergic receptor (β-AR) stimulation. The aim of this study was to measure the contribution of the Ca clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation.
METHODS AND RESULTS—We used the L-type Ca channel agonist Bay K8644 (BayK) to activate the SANC Ca clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from wild-type control mice. In contrast, SANCs and isolated hearts from mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs but increased L-type Ca current (ICa) equally in all SANCs, indicating that increasing ICa was insufficient and suggesting that CaMKII activation was required for heart rate increases by BayK. BayK did not increase If or protein kinase A-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca by BayK did not augment cAMP/protein kinase A signaling at these targets. Late-diastolic intracellular Ca release and INCX were significantly reduced in AC3-I SANCs, and the response to BayK was eliminated by ryanodine in all groups.
CONCLUSIONS—The Ca clock is capable of supporting physiological fight-or-flight responses, independent of β-AR stimulation or If increases. Complete Ca clock and β-AR stimulation responses require CaMKII.
The National Institute of Standards and Technology, the U.S. Food and Drug Administration, Center for Drug Evaluation and Research and Center for Food Safety and Applied Nutrition, and the National ...Institutes of Health, Office of Dietary Supplements, are collaborating to produce a series of Standard Reference Materials (SRMs) for dietary supplements. A suite of ephedra materials is the first in the series, and this paper describes the acquisition, preparation, and value assignment of these materials: SRMs 3240 Ephedra sinica Stapf Aerial Parts, 3241 E. sinica Stapf Native Extract, 3242 E. sinica Stapf Commercial Extract, 3243 Ephedra-Containing Solid Oral Dosage Form, and 3244 Ephedra-Containing Protein Powder. Values are assigned for ephedrine alkaloids and toxic elements in all 5 materials. Values are assigned for other analytes (e.g., caffeine, nutrient elements, proximates, etc.) in some of the materials, as appropriate. Materials in this suite of SRMs are intended for use as primary control materials when values are assigned to in-house (secondary) control materials and for validation of analytical methods for the measurement of alkaloids, toxic elements, and, in the case of SRM 3244, nutrients in similar materials.
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