Assessment of the physiological effects and safety of transpulmonary chemoembolization with doxorubicin on pulmonary tissue using a human-isolated lung perfusion model.

Background: Whole lung transpulmonary chemoembolization using a combination of doxorubicin (DXO) and degradable starch microspheres (DSM-TPCE) might be a promising treatment option in soft tissue sarcoma. To pave the way for clinical studies, this study aimed to evaluate the short-term effects of DSM-TPCE with DXO using an ex vivo isolated lung perfusion (ILP) model.

Methods: Nine lung specimens retrieved from patients undergoing lobectomy underwent ex vivo ILP.

Hardware and software solutions for implementing nanospray desorption electrospray ionization (nano-DESI) sources on commercial mass spectrometers.

Nanospray desorption electrospray ionization (nano-DESI) is an ambient ionization mass spectrometry imaging (MSI) approach that enables spatial mapping of biological and environmental samples with high spatial resolution and throughput. Because nano-DESI has not yet been commercialized, researchers develop their own sources and interface them with different commercial mass spectrometers. Previously, several protocols focusing on the fabrication of nano-DESI probes have been reported.

Population pharmacokinetic modeling of treosulfan and rationale for dose recommendation in children treated for conditioning prior to allogeneic hematopoietic stem cell transplantation.

Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update the initial population PK model by inclusion of additional 83 pediatric PK profiles from these 2 trials.

Nanospray Desorption Electrospray Ionization (Nano-DESI) Mass Spectrometry Imaging with High Ion Mobility Resolution.

Untargeted separation of isomeric and isobaric species in mass spectrometry imaging (MSI) is challenging. The combination of ion mobility spectrometry (IMS) with MSI has emerged as an effective strategy for differentiating isomeric and isobaric species, which substantially enhances the molecular coverage and specificity of MSI experiments. In this study, we have implemented nanospray desorption electrospray ionization (nano-DESI) MSI on a trapped ion mobility spectrometry (TIMS) mass spectrometer.

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters.

T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3.

High-Throughput Mass Spectrometry Imaging with Dynamic Sparse Sampling.

Mass spectrometry imaging (MSI) enables label-free mapping of hundreds of molecules in biological samples with high sensitivity and unprecedented specificity. Conventional MSI experiments are relatively slow, limiting their utility for applications requiring rapid data acquisition, such as intraoperative tissue analysis or 3D imaging. Recent advances in MSI technology focus on improving the spatial resolution and molecular coverage, further increasing the acquisition time.

Evaluation of the drug-drug interaction potential of treosulfan using a physiologically-based pharmacokinetic modelling approach.

Aims: The aim of this work is the development of a mechanistic physiologically-based pharmacokinetic (PBPK) model using in vitro to in vivo extrapolation to conduct a drug-drug interaction (DDI) assessment of treosulfan against two cytochrome p450 (CYP) isoenzymes and P-glycoprotein (P-gp) substrates.

Methods: A PBPK model for treosulfan was developed de novo based on literature and unpublished clinical data. The PBPK DDI analysis was conducted using the U.

The effect of the triazene compound CT913 on ovarian cancer cells in vitro and its synergistic interaction with the PARP-inhibitor olaparib.

Objectives: Extending the therapeutic spectrum of PARP-inhibitors (PARPi) beyond BRCA1-deficiency and/or overcoming PARPi-resistance is of high clinical interest. This is particularly true for the identification of innovative therapeutic strategies for ovarian cancer, given the recent advances in the use of PARPi in clinical practice. In this regard, the combination of PARPi with chemotherapy is a possible strategy for defining new therapeutic standards.

High-throughput screening of organic reactions in microdroplets using desorption electrospray ionization mass spectrometry (DESI-MS): hardware and software implementation.

This study describes an automated system used for high throughput screening of reaction conditions based on accelerated reactions occurring in small volumes of reagents. Reaction mixtures are prepared in array format using a fluid handling robot and spotted on a flat polytetrafluoroethylene plate at densities up to 6144 per plate. The reaction and analysis steps are performed simultaneously using desorption electrospray ionization (DESI) to release microdroplets containing the reaction mixture from the plate for reaction prior to arrival at a mass spectrometer.

Correction: Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature.

[This corrects the article DOI: 10.1371/journal.pone.

Diphenhydramine increases the therapeutic window for platinum drugs by simultaneously sensitizing tumor cells and protecting normal cells.

Platinum-based compounds remain a well-established chemotherapy for cancer treatment despite their adverse effects which substantially restrict the therapeutic windows of the drugs. Both the cell type-specific toxicity and the clinical responsiveness of tumors have been associated with mechanisms that alter drug entry and export. We sought to identify pharmacological agents that promote cisplatin (CP) efficacy by augmenting the levels of drug-induced DNA lesions in malignant cells and simultaneously protecting normal tissues from accumulating such damage and from functional loss.

Integration of a Multichannel Pulsed-Valve Inlet System to a Linear Quadrupole Ion Trap Mass Spectrometer for the Rapid Consecutive Introduction of Nine Reagents for Diagnostic Ion/Molecule Reactions.

Gas-phase ion/molecule reactions have been used extensively for the structural elucidation of organic compounds in tandem mass spectrometry. Reagents for ion/molecule reactions can be introduced into a mass spectrometer via a continuous flow apparatus or through a pulsed inlet system. However, most of these approaches enable the use of only a single reagent at a time.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m/day (BSA ≤ .

Implementation of Precursor and Neutral Loss Scans on a Miniature Ion Trap Mass Spectrometer and Performance Comparison to a Benchtop Linear Ion Trap.

Implementation of orthogonal double resonance precursor and neutral loss scans on the Mini 12 miniature rectilinear ion trap mass spectrometer is described, and performance is compared to that of a commercial Thermo linear trap quadropole (LTQ) linear ion trap. The ac frequency scan version of the technique at constant rf voltage is used here because it is operationally much simpler to implement. Remarkably, the Mini 12 shows up to two orders of magnitude higher sensitivity compared to that of the LTQ.

Precursor and Neutral Loss Scans in an RF Scanning Linear Quadrupole Ion Trap.

Methodology for performing precursor and neutral loss scans in an RF scanning linear quadrupole ion trap is described and compared to the unconventional ac frequency scan technique. In the RF scanning variant, precursor ions are mass selectively excited by a fixed frequency resonance excitation signal at low Mathieu q while the RF amplitude is ramped linearly to pass ions through the point of excitation such that the excited ion's m/z varies linearly with time. Ironically, a nonlinear ac frequency scan is still required for ejection of the product ions since their frequencies vary nonlinearly with the linearly varying RF amplitude.

High users of healthcare: Strategies to improve care, reduce costs.

A minority of patients consume a disproportionate amount of healthcare, especially in the emergency department. These "high users" are a small but complex group whose expenses are driven largely by low socioeconomic status, mental illness, and drug abuse; lack of social services also contributes. Several promising efforts aimed at improving quality and reducing healthcare costs for high users include care management organizations, patient care plans, and better discharge summaries.

Validation of a Commercial Assay and Decision Support Tool for Routine Paclitaxel Therapeutic Drug Monitoring (TDM).

Background: The value of therapeutic drug monitoring (TDM) for paclitaxel (PTX) was recently demonstrated in the largest TDM trial ever conducted in oncology. The trial demonstrated significant reduction in neuropathy when using TDM. Dose adjustment for PTX was based on time above a threshold concentration (Tc>0.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

Background: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure.

Patients And Methods: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B).

Improved Treatment of MT-3 Breast Cancer and Brain Metastases in a Mouse Xenograft by LRP-Targeted Oxaliplatin Liposomes.

The anti-cancer drug oxaliplatin (OxP) has rarely been used to treat breast carcinoma, as it cannot cross the BBB to treat the frequently subsequent brain metastases. Here, we encapsulated OxP in liposomes prepared to reduce side effects and to simultaneously treat primary tumor and brain metastasis. The angiopep LRP-receptor ligand was bound to the vesicular surface for targeting.

Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance.

Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3).

Safety, tolerability and pharmacokinetic properties of the novel triazene TriN 2755 in tumour bearing dogs - a phase I study.

TriN 2755 is an alkylating antineoplastic agent for intravenous (IV) use, carrying the triazene group as the cytotoxic principal. Using a standard 3 + 3 design, a phase I study was performed in tumour bearing dogs to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and pharmacokinetic (PK) profile of TriN 2755. Thirty dogs were included in the study.

Electroosmotically driven solution mixing in borosilicate theta glass nESI emitters.

The use of borosilicate theta glass capillaries as nanoelectrospray ionization emitters has recently been demonstrated as a method for mixing two solutions as they are sprayed into the mass spectrometer for analysis. All previous experiments resulted in a solution mixing timescale limited to the time the analytes spend in the Taylor cone and subsequent droplets (i.e.

Tandem mass spectrometry in an electrostatic linear ion trap modified for surface-induced dissociation.

A variety of ion traps are used in mass spectrometry. A key feature shared by most of them is the ability to perform tandem mass spectrometry (MS/MS). The Orbitrap is perhaps the most notable ion trap in which MS/MS has yet to be performed.

Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma.

Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis.