Is there a role for dual PI3K/mTOR inhibitors for patients affected with lymphoma?

The activation of the PI3K/AKT/mTOR pathway is a main driver of cell growth, proliferation, survival, and chemoresistance of cancer cells, and, for this reason, represents an attractive target for developing targeted anti-cancer drugs. There are plenty of preclinical data sustaining the anti-tumor activity of dual PI3K/mTOR inhibitors as single agents and in combination in lymphomas. Clinical responses, including complete remissions (especially in follicular lymphoma patients), are also observed in the very few clinical studies performed in patients that are affected by relapsed/refractory lymphomas or chronic lymphocytic leukemia. In this review, we summarize the literature on dual PI3K/mTOR inhibitors focusing on the lymphoma setting, presenting both the three compounds still in clinical development and those with a clinical program stopped or put on hold

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

Benthic trophic interactions in an Antarctic shallow water ecosystem affected by recent glacier retreat

The western Antarctic Peninsula is experiencing strong environmental changes as a consequence of ongoing regional warming. Glaciers in the area are retreating rapidly and increased sediment-laden meltwater runoff threatens the benthic biodiversity at shallow depths. We identified three sites with a distinct glacier-retreat related history and different levels of glacial influence in the inner part of Potter Cove (King George Island, South Shetland Islands), a fjord-like embayment impacted since the 1950s by a tidewater glacier retreat. We compared the soft sediment meio- and macrofauna isotopic niche widths (d13C and d15N stable isotope analysis) at the three sites to investigate possible glacier retreat-related influences on benthic trophic interactions. The isotopic niches were locally shaped by the different degrees of glacier retreat-related disturbance within the Cove. Wider isotopic niche widths were found at the site that has become ice-free most recently, and narrower niches at the older ice-free sites. At an intermediate state of glacier retreat-related disturbance (e.g. via ice-growler scouring) species with different strategies could settle. The site at the earliest stage of post-retreat development was characterized by an assemblage with lower trophic redundancy. Generally, the isotopic niche widths increased with increasing size spectra of organisms within the community, excepting the youngest assemblage, where the pioneer colonizer meiofauna size class displayed the highest isotopic niche width. Meiofauna at all sites generally occupied positions in the isotopic space that suggested a detrital-pool food source and/or the presence of predatory taxa. In general ice scour and glacial impact appeared to play a two-fold role within the Cove: i) either stimulating trophic diversity by allowing continuous re-colonization of meiofaunal species or, ii) over time driving the benthic assemblages into a more compact trophic structure with increased connectedness and resource recycling

Giant intermolecular decay and fragmentation of clusters. Phys

In sharp contrast to molecules, electronic states of clusters with an excited intermediate-shell electron can efficiently decay via an intermolecular Coulombic mechanism. Explicit examples are presented using large scale ab initio propagator calculations. The mechanism is illustrated and its generality is stressed. [S0031-9007(97) PACS numbers: 36.40. Cg, 31.50. + w, 34.50.Gb Quantum states of electronic systems typically decay by photon and/or electron emission. Energetically low lying states decay radiatively while highly excited levels involving the excitation of inner-shell electrons decay more efficiently by emitting an electron (Auger decay). It is only for very deep inner-shell electrons of heavy elements that x-ray emission constitutes the prominent decay channel As mentioned above, the environment of the atom influences only moderately the lifetime of the deep vacancy (e.g., of a F1s vacancy). If at all, we can only expect interesting environmental effects on the total Auger decay rate to take place for vacancies in intermediate shells. However, a closer look at the energetics of the decay in typical molecules brings a problem to light. The ionization potential (IP) of a F2s electron in, say, the HF molecule, is about 40 eV Atomic and molecular clusters have been subject to continuous interest over many years We propose to use a different approach. The groups involved in the present study have acquired considerable experience in the ab initio computation of ionization The ionization and Auger spectra of several monomers and clusters have been computed using the methods described in Refs

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

Theoretical investigations of molecular triple ionization spectra

Triple ionization of molecular systems is investigated theoretically by means of the three-particle propagator. This enables us to efficiently calculate the very dense triple ionization spectra. To be able to interpret these spectra an atomic three-hole population analysis is developed which provides information about the charge distribution in the molecular trication. In exemplary applications on CO and a series of fluorides the use of the approach is demonstrated. A large number of triply ionized electronic states are energetically accessible in the available particle impact ionization experiments and it is shown that many of these states contribute to the observations. Triply ionized states are also produced by Auger decay. In particular, shake-off satellite lines of molecular Auger spectra can be reproduced using the triple ionization energies from the propagator calculation and an estimate of the transition rates based on the three-hole population analysis. In general a dramatically growing complexity of the triple ionization spectra with increasing molecular size is demonstrated. In spite of this complexity the three-hole population analysis is of valuable help for the interpretation of the spectra and often a simple picture in terms of various hole-localization patterns arises

Implementation of script-cognitive and neural network modeling of water treatment processes

Проведен критический анализ существующих европейских нормативных документов оценки экологической безопасности водных ресурсов в контексте эффективности удаления загрязнителей из водных ресурсов. Обоснована методика сценарно-когнитивного и нейросетевого моделирования процессов комбинированной водоочистки с использованием нечетких когнитивных карт и многослойных персептронов и формированием энергоэффективных выборок. Такие наборы данных являются базисом для формирования соответствующих интеллектуальных решений. Практически реализовано сценарно- когнитивное (нечеткие когнитивные карты) и нейросетевое (многослойный персептрон) моделирование процессов водоочистки с использованием прикладного программного продукта FCMapper. Подтверждены технологические и экологические приемлемости использования созданных математических моделей (относительные ошибки): учебная выборка – 2,7 %, контрольная выборка – 2,9 %, тестовая выборка – 3,05 %. Имитационная оценка качества функционирования интеллектуальных моделей, выполненная в среде MatLAB, продемонстрировала, что математическое обеспечение достигает необходимой энергоэффективности и позволяет управлять экологической безопасностью комбинированных систем водоочистки: относительная ошибка реакции системы при выходе на заданное значение – 3,82 %. Определено, что дальнейшие исследования целесообразно направить на формирование репрезентативных выборок для формирования интеллектуальных решений описания процессов удаления загрязнителей из стоков, что повысило бы их управляемость и экологическую безопасность.A critical analysis of the existing European regulatory documents for assessing the environmental safety of water resources in the context of the efficiency of removing pollutants from water resources was carried out. The article substantiates the technique of script-cognitive and neural network modeling of combined water treatment processes using fuzzy cognitive maps and multilayer perceptrons and generating energy efficient sample. Such datasets are the basis for the formation of appropriate intelligent solutions. Scriptcognitive (fuzzy cognitive maps) and neural network (multilayer perceptron) modeling of water treatment processes using the FCMapper application software are practically implemented. The technological and environmental acceptability of using the created mathematical models (relative errors) has been confirmed: training sample – 2.7%, control sample – 2.9%, test sample – 3.05%. The imitation assessment of the quality of functioning of intelligent models, carried out in the MatLAB environment, has demonstrated that the software achieves the required energy efficiency and enables managing the environmental safety of combined water treatment systems: relative error of the system reaction when reaching the set value – 3.82%. It was determined that further research should be directed to the formation of representative samples for the formation of intelligent solutions for describing the processes of removing pollutants from effluents, which would increase their controllability and environmental safety

Autoionization widths by Stieltjes imaging applied to Lanczos pseudospectra

Excited states of atoms and molecules lying above the ionization threshold can decay by electron emission in a process commonly known as autoionization. The autoionization widths can be calculated conveniently using Fano formalism and discretized atomic and molecular spectra by a standard procedure referred to as Stieltjes imaging. The Stieltjes imaging procedure requires the use of the full discretized spectrum of the final states of the autoionization, making its use for poly-atomic systems described by high-quality basis sets impractical. Following our previous work on photoionization cross-sections, here we show that also in the case of autoionization widths, the full diagonalization bottleneck can be overcome by the use of Lanczos pseudospectra. We test the proposed method by calculating the well-documented autoionization widths of inner-valence-excited neon and apply the new technique to autoionizing states of hydrofluoric acid and benzene