Antibody-drug conjugates for lymphoma patients: preclinical and clinical evidences

Antibody-drug conjugates (ADCs) are a recent, revolutionary approach for malignancies treatment, designed to provide superior efficacy and specific targeting of tumor cells, compared to systemic cytotoxic chemotherapy. Their structure combines highly potent anti-cancer drugs (payloads or warheads) and monoclonal antibodies (Abs), specific for a tumor-associated antigen, via a chemical linker. Because the sensitive targeting capabilities of monoclonal Abs allow the direct delivery of cytotoxic payloads to tumor cells, these agents leave healthy cells unharmed, reducing toxicity. Different ADCs have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of a wide range of malignant conditions, both as monotherapy and in combination with chemotherapy, including for lymphoma patients. Over 100 ADCs are under preclinical and clinical investigation worldwide. This paper provides an overview of approved and promising ADCs in clinical development for the treatment of lymphoma. Each component of the ADC design, their mechanism of action, and the highlights of their clinical development progress are discussed

The Born-Oppenheimer Approach to the Matter-Gravity System and Unitarity

The Born-Oppenheimer approach to the matter-gravity system is illustrated and the unitary evolution for matter, in the absence of phenomena such as tunnelling or other instabilities, verified. The Born-Oppenheimer approach to the matter-gravity system is illustrated in a simple minisuperspace model and the corrections to quantum field theory on a semiclassical background exhibited. Within such a context the unitary evolution for matter, in the absence of phenomena such as tunnelling or other instabilities, is verified and compared with the results of other approaches. Lastly the simplifications associated with the use of adiabatic invariants to obtain the solution of the explicitly time dependent evolution equation for matter are evidenced.Comment: Latex, 12 pages. Revised version as accepted for publication by Class. and Quant. Grav. Some points explained and misprints correcte

Ionospheric perturbations in possible association with the 2010 Haiti earthquake, as based on medium-distance subionospheric VLF propagation data

Ionospheric perturbations in possible association with the 2010 Haiti earthquake occurred on 12 January 2010 (with a magnitude of 7.0 and depth of 10 km) are investigated on the basis of subionospheric propagation data from the NAA transmitter on the east coast of the USA to a VLF receiving station in Peru. The local nighttime VLF amplitude data are extensively investigated during the period from the beginning of October 2009 to the end of March 2010, in which the trend (nighttime average amplitude), dispersion and nighttime fluctuation are analysed. It is found that a clear precursory ionosphere perturbation is detected just around New Years day of 2010, about 12 days before the main shock, which is characterised by the simultaneous decrease in the trend and the increases in dispersion and nighttime fluctuation. An additional finding might be the presence of the effect of the Earth's tide one and two months before the main shock, which can only be seen for a huge EQ

Recurrence of the oxazole motif in tubulin colchicine site inhibitors with anti-tumor activity

Because of its wide spectrum of targets and biological activities, the oxazole ring is a valuable heterocyclic scaffold in the design of new therapeutic agents with anticancer, antiviral, antibacterial, anti-inflammatory, neuroprotective, antidiabetic and antidepressant properties. The presence of two heteroatoms, oxygen and nitrogen, offers possible interactions (hydrogen, hydrophobic, van der Waals or dipoles bonds) with a broad range of receptors and enzymes. Furthermore, the oxazole core conjugates low cytotoxicity with improved compound solubility and is well suited to structural modifications such as substitution with different groups and condensation to aromatic, heteroaromatic or non-aromatic rings, offering diversity when introduced into scaffolds. These features make it a very attractive nucleus in medicinal chemistry. Herein we present a diverse array of oxazole derivatives with potential therapeutic use in multiple tumor models. The emphasis has been addressed to compounds with anti-tubulin activity reported in literature in the last decade, describing their structural features, efficiency and future perspectives

Immune-related adverse events in the treatment of non-Hodgkin lymphoma with immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) show efficacy in the treatment of non-Hodgkin lymphomas (NHL). However, these agents are associated with a unique group of side effects called immune-related adverse events (irAEs). We conducted an observational retrospective/prospective study on patients with relapsed/refractory NHL treated with ICI to determine the incidence of irAEs assessing the type, severity, and timing of onset, outcome and relationship with study drugs of these events. Thirty-two patients underwent ICI as single agent (N = 20) or in combination (N = 12). Ten patients (31.3%) developed at least one irAE for a total of 17 irAEs. Median time to presentation of irAEs was 69 days (range 0–407) with a median resolution time of 16 days (range 0–98). Progression free survival at 24 months for patients who developed an irAE was 40% and 31.8% for who did not. Overall survival for the two groups did not differ (at 24 months 40.0% and 62.5% for patients without and with irAE, respectively), but the median for who developed an irAE was not reached. The incidence of irAEs was associated with better long-term survival in NHL treated with ICIs but patients’ disease conditions need to be carefully evaluated to decide the optimal management

Single-qubit gates and measurements in the surface acoustic wave quantum computer

In the surface acoustic wave quantum computer, the spin state of an electron trapped in a moving quantum dot comprises the physical qubit of the scheme. Via detailed analytic and numerical modeling of the qubit dynamics, we discuss the effect of excitations into higher-energy orbital states of the quantum dot that occur when the qubits pass through magnetic fields. We describe how single-qubit quantum operations, such as single-qubit rotations and single-qubit measurements, can be performed using only localized static magnetic fields. The models provide useful parameter regimes to be explored experimentally when the requirements on semiconductor gate fabrication and the nanomagnetics technology are met in the future.Comment: 13 pages, 10 figures, submitted to Phys. Rev.

IRI-2001 model predictions compared with ionospheric data observed at Brazilian low latitude stations

International audienceIn this work, the F-region critical frequency (foF2) and peak height (hmF2) measured by digital ionosondes at two Brazilian low-latitude stations, namely Palmas (10.17° S, 48.20° W, dip ?10.80°) and São José dos Campos (23.20° S, 45.86° W, dip ?38.41°), are compared with the IRI-2001 model predictions. The comparison at the latter station shows quite a reasonable agreement for both parameters. The former station exhibits a better agreement for hmF2 than for foF2. In general, the model generates good results, although some improvements are still necessary to implement in order to obtain better simulations for equatorial ionospheric regions

Hamiltonian formalism for the Oppenheimer-Snyder model

A family of effective actions in Hamiltonian form is derived for a self-gravitating sphere of isotropic homogeneous dust. Starting from the Einstein-Hilbert action for barotropic perfect fluids and making use of the symmetry and equation of state of the matter distribution we obtain reduced actions for two canonical variables, namely the radius of the sphere and its ADM energy, the latter being conserved along trajectories of the former. These actions differ by the value of the (conserved) geodesic energy of the radius of the sphere which defines (disconnected) classes of solutions in correspondence to the inner geometry and proper volume of the sphere. Each class is thus treated as one constrained dynamical system and the union of all classes covers the full phase space of the model. Generalization to the (inhomogeneous) Tolman model is shown to be straightforward. Quantization is also discussed.Comment: RevTeX, 10 pages, no figure

First Very Low Frequency detection of short repeated bursts from magnetar SGR J1550-5418

We report on the first detection of ionospheric disturbances caused by short repeated gamma-ray bursts from the magnetar SGR J1550-5418. Very low frequency (VLF) radio wave data obtained in South America clearly show sudden amplitude and phase changes at the corresponding times of eight SGR bursts. Maximum amplitude and phase changes of the VLF signals appear to be correlated with the gamma-ray fluence. On the other hand, VLF recovery timescales do not show any significant correlation with the fluence, possibly suggesting that the bursts' spectra are not similar to each other. In summary, the Earth's ionosphere can be used as a very large gamma-ray detector and the VLF observations provide us with a new method to monitor high energy astrophysical phenomena without interruption such as Earth Occultation.Comment: 14 pages, 4 figures, accepted by ApJ