Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM.

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects.

Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis.

Background: Anti-programmed cell death ligand 1 (PD-L1)/programmed cell death 1 antibodies have shown clinical activity in platinum-treated metastatic urothelial carcinoma, resulting in regulatory approval of several agents, including avelumab (anti-PD-L1). We report ≥2-year follow-up data for avelumab treatment and exploratory subgroup analyses in patients with urothelial carcinoma.

Methods: Patients with previously treated advanced/metastatic urothelial carcinoma, pooled from two cohorts of the phase Ib JAVELIN Solid Tumor trial, received avelumab 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity or withdrawal.

A chemical, crystallographic and magnetic characterisation of individual iron-oxide grains in Hawaiian lavas.

Our knowledge on the behaviour of the geomagnetic field through time critically depends on how information of the past state of the field is recorded by, and stored in iron-bearing minerals such as magnetite. For small, single domain grains these processes are described by classical Néel theory, but the magnetic behaviour of larger, pseudo-single domain or multidomain grains, still is enigmatic. Here we present a chemical, crystallographic and magnetic characterisation of three to six individual, large (~3-10 μm) iron-oxide grains from eleven different flows sampled on the Big Island of Hawai'i.

Microscale cavitation as a mechanism for nucleating earthquakes at the base of the seismogenic zone.

Major earthquakes frequently nucleate near the base of the seismogenic zone, close to the brittle-ductile transition. Fault zone rupture at greater depths is inhibited by ductile flow of rock. However, the microphysical mechanisms responsible for the transition from ductile flow to seismogenic brittle/frictional behaviour at shallower depths remain unclear.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

Background: Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma.

The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment.

Unlabelled: Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival.

An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours.

Background: Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours.

Methods: In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10mg/kg) for 1h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks.

Nanodiamonds and wildfire evidence in the Usselo horizon postdate the Allerod-Younger Dryas boundary.

The controversial Younger Dryas impact hypothesis suggests that at the onset of the Younger Dryas an extraterrestrial impact over North America caused a global catastrophe. The main evidence for this impact--after the other markers proved to be neither reproducible nor consistent with an impact--is the alleged occurrence of several nanodiamond polymorphs, including the proposed presence of lonsdaleite, a shock polymorph of diamond. We examined the Usselo soil horizon at Geldrop-Aalsterhut (The Netherlands), which formed during the Allerød/Early Younger Dryas and would have captured such impact material.

Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.

Purpose: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies.

Experimental Design: p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions.

Patient responses to ipilimumab, a novel immunopotentiator for metastatic melanoma: how different are these from conventional treatment responses?

Advanced melanoma has defied treatment advances for several decades. Immunotherapy with high-dose interleukin-2 or interferon-α has been beneficial in some cases, but significant toxicities limit its use. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling switches off T-cell activation and induces immune tolerance.

Cryogenic EBSD on ice: preserving a stable surface in a low pressure SEM.

Naturally deformed ice contains subgrains with characteristic geometries that have recently been identified in etched surfaces using high-resolution light microscopy (LM). The probable slip systems responsible for these subgrain boundary types can be determined using electron backscattered diffraction (EBSD), providing the etch features imaged with reflected LM can be retained during EBSD data acquisition in a scanning electron microscope (SEM). Retention of the etch features requires that the ice surface is stable.

Electron backscattered diffraction as a tool to quantify subgrains in deformed calcite.

In this work, we investigated processing methods to obtain subgrain sizes from electron backscattered diffraction data using samples of experimentally deformed calcite (CaCO(3)) polycrystals. The domain boundary hierarchy method, based on area measurements of domains enclosed by boundaries larger than a given misorientation angle, was applied to these calcite samples and was found to be limited by: (i) topological problems; (ii) undersampling of large grains; and (iii) artefacts caused by nonindexing. We tested two alternative methods that may reduce the problems: (i) the measured linear intercept hierarchy method, based on measurements of linear intercept between boundaries having larger misorientations than a given minimum angle; and (ii) the calculated linear intercept hierarchy method, based on the total length of boundaries having misorientations larger than a given minimum angle.

Low-angle subgrain misorientations in deformed NaCl.

The development of subgrain boundary misorientations with strain in NaCl polycrystals has been investigated. At low strains, a power law relationship exists between strain and average misorientations. The accuracy of this relationship is assessed in terms of material and electron backscattered diffraction (EBSD) processing parameters and is found to hold for a material of constant grain size deformed in compression, providing EBSD mapping and processing conditions were similar.

Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure.

Thyroid hormone has unique actions that make it a novel and possibly useful agent for treatment of heart failure. Because of potential adverse effects of thyroid hormone, however, there has been interest in developing analogues with fewer undesirable side effects. Screening of compounds structurally related to levothyroxine identified 3,5-diiodothyropropionic acid (DITPA) as an analogue with inotropic selectivity and low metabolic activity in hypothyroid rats.

Pilot studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure.

After an initial safety study in 7 normal volunteers, a randomized double-blind comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in 19 patients with moderately severe congestive failure. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.

Misorientation distributions in hot deformed NaCl using electron backscattered diffraction.

EBSD orientation mapping has been used to derive subgrain boundary misorientation distributions in a series of hot deformed and etched NaCl samples. The main objective of this study has been to examine the influence of data processing, noise caused by angular resolution limits and step size on the subgrain misorientation distributions in hot deformed NaCl. Processing of non-indexed EBSD patterns increased the average misorientations in etched NaCl.

Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA).

Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca(2+)transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca(2+)transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.

DITPA prevents the blunted contraction-frequency relationship in myocytes from infarcted hearts.

Loss of the positive force-frequency relationship is a characteristic finding in failing hearts. The mechanisms of this change are not well understood. Myocardial infarction (MI) was induced in rabbits to produce left ventricular (LV) dysfunction.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

We analyzed transesophageal echocardiograms from 772 participants in the Stroke Prevention in Atrial Fibrillation (SPAF-III) study, characterizing spontaneous echocardiographic contrast (SEC) in the left atrium or appendage as faint or dense. The association of dense SEC with stroke risk factors and anatomic, hemodynamic, and hemostatic parameters related to specific thromboembolic mechanisms was evaluated by multivariate analysis. Spontaneous echocardiographic contrast was present in 55% of patients and was dense in 13%.

Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal echocardiography.

Patients with atrial fibrillation and with documented aortic plaque who were assigned to adjusted-dose warfarin therapy (international normalized ratio 2.0 to 3.0) had an annual rate of cholesterol embolization of 0.

Left atrial diameter in nonvalvular atrial fibrillation: An echocardiographic study. Stroke Prevention in Atrial Fibrillation Investigators.

Background: The left atrium (LA) is usually enlarged in patients with nonvalvular atrial fibrillation (AF), but factors associated with LA diameter are incompletely defined.

Methods And Results: This transthoracic echocardiographic cohort study includes 3465 participants with nonvalvular AF in 3 multicenter clinical trials. LA diameter determined by M-mode echocardiography was correlated with clinical and echocardiographic features by cross-sectional multivariate regression analyses.

Increased intraventricular velocities: an unrecognized cause of systolic murmur in adults.

Objectives: The purpose of this study was to determine the frequency, clinical features and echocardiographic characteristics of increased intraventricular velocities (IIVs) in patients referred to the echocardiography laboratory for systolic murmur.

Background: A subset of patients referred to the echocardiography laboratory for evaluation of a systolic murmur have IIVs in the absence of other recognized causes of systolic murmur.

Methods: We prospectively studied echocardiograms from 108 consecutive patients referred for evaluation of a systolic murmur.