COVID-19. Aetiology, pathogenesis, diagnosis and treatment

COVID-19 (Coronavirus disease 2019) is a new epidemic infectious disease characterized by a relatively high contagiousness and a high probability of life-threatening complications such as acute respiratory distress syndrome (ARDS), acute respiratory and multiple organ failure. The causative agent of the disease is the enveloped zoonotic RNA virus known as SARS-CoV-2. Together with the SARS-CoV and MERS-CoV viruses, which cause severe acute respiratory syndrome and the Middle East respiratory syndrome, respectively, it belongs to the Coronaviridae family, the genus Betacoronavirus. The COVID-19 epidemic has spread rapidly around the world and currently hit 213 countries with more than 1.6 million confirmed cases, of which more than 90.000 have died so far. In Russian Federation, SARS-CoV-2 infection is included in the list of diseases that pose a danger to others, along with especially dangerous infections. The virus is transmitted by airborne droplets, airborne dust and contact routes, therefore, to protect medical staff it is necessary to use individual protective suits and accessories, with protection of the respiratory tract and eyes, disinfection of hands and surfaces as when working with the BSL-2 microorganisms. The diagnosis of COVID-19 is confirmed using real-time RT-PCR diagnostics detecting the presence of viral RNA. Clinical manifestations of COVID-19 vary from mild and moderate (pneumonia without signs of hypoxemia and impaired O2 saturation, 80% of all cases), to severe (15% of cases, O2 saturation 8993%) and extremely severe (5% of cases, ARDS, multiple organ failure, mechanical ventilation and resuscitation are necessary). The typical clinical presentation of COVID19 patients includes the following: severe fever, dry cough, respiratory failure, combined with lymphopenia and thrombocytopenia, normal procalcitonin, elevated levels of ferritin and CRP in the blood with signs of bilateral, polysegmental pneumonia and the ground glass opacity on CT. Even in the absence of an unfavorable epidemiological anamnesis, these clinical signs can be recommended to admit the patient to an infectious isolation ward where he or she would wait for the results of PCR diagnostics and the diagnosis of COVID-19 be confirmed/ ruled out. Currently, no SARS-CoV-2-specific therapy is available for COVID-19 patients; the only method that has proven effective in several investigational trials is transfusion of convalescent plasma with high titers of neutralizing antibodies. A number of innovative treatments appear promising and include the use of neutralizing monoclonal antibodies, ACE2-derived agents, as well as MSC- and NK-cell based cell therapies

Comparative analysis of lactaptin activity when produced in bacterial or eukaryotic expression systems

Despite the multitude of anticancer cytostatic drugs available to oncologists today, most of such drugs have serious side effects that may preclude their use in some groups of patients. Hence, selective induction of apoptosis in cancer but not normal cells remains an attractive goal of molecular medicine. Lactaptin, a proteolytic fragment of the human milk kappa-casein, has been previously identified as a protein displaying potent killing of cancer cells in vitro. Its recombinant analog (RL2) produced in E. coli has been shown to delay solid tumor growth in vivo. Given that lactaptin is of human origin and is not immunogenic, it can be administered to patients multiple times without running the risk of immune response that could dampen the therapy efficacy. In the present study, we demonstrate that the combination of RL2 and cyclophosphamide treatments has an additive therapeutic effect against hepatoma tumor in immunocompetent mice. We asked whether production of lactaptin in human rather than bacterial cells would result in a protein with increased cytotoxic activity. Using lentiviral vector pCDH as a backbone, two constructs, pEL1 and pEL2, encoding secreted forms of lactaptin that differ in their signal sequences were created. Lactaptin expression in human cell lines was confirmed using Western-blot analysis, whereas ELISA was used for quantification of secreted lactaptin. Next, we measured the cytotoxic effects of the media conditioned by pEL1-transfected HEK293T cells, as assayed against the panel of three human cancer cell lines: MDA-MB-231 (adenocarcinoma), PC3 (prostate cancer), and T98G (glioblastoma). We show that EL1-derived lactaptin is at least 100-fold more cytotoxic than RL2. Taken together, our results provide an opportunity for developing armored immune cells as an “off-the-shelf” platform for targeted delivery of lactaptin to cancer cells

CAR-T cell. the long and winding road to solid tumors

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the "next generation" of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host's defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles

Properties of Heavy Secondary Fluorine Cosmic Rays: Results from the Alpha Magnetic Spectrometer

Precise knowledge of the charge and rigidity dependence of the secondary cosmic ray fluxes and the secondary-to-primary flux ratios is essential in the understanding of cosmic ray propagation. We report the properties of heavy secondary cosmic ray fluorine F in the rigidity R range 2.15 GV to 2.9 TV based on 0.29 million events collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The fluorine spectrum deviates from a single power law above 200 GV. The heavier secondary-to-primary F/Si flux ratio rigidity dependence is distinctly different from the lighter B/O (or B/C) rigidity dependence. In particular, above 10 GV, the F/SiB/O ratio can be described by a power law Rδ with δ=0.052±0.007. This shows that the propagation properties of heavy cosmic rays, from F to Si, are different from those of light cosmic rays, from He to O, and that the secondary cosmic rays have two classes

Properties of Iron Primary Cosmic Rays: Results from the Alpha Magnetic Spectrometer

We report the observation of new properties of primary iron (Fe) cosmic rays in the rigidity range 2.65 GV to 3.0 TV with 0.62 million iron nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. Above 80.5 GV the rigidity dependence of the cosmic ray Fe flux is identical to the rigidity dependence of the primary cosmic ray He, C, and O fluxes, with the Fe/O flux ratio being constant at 0.155±0.006. This shows that unexpectedly Fe and He, C, and O belong to the same class of primary cosmic rays which is different from the primary cosmic rays Ne, Mg, and Si class

Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen

We report the properties of sodium (Na) and aluminum (Al) cosmic rays in the rigidity range 2.15 GV to 3.0 TV based on 0.46 million sodium and 0.51 million aluminum nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. We found that Na and Al, together with nitrogen (N), belong to a distinct cosmic ray group. In this group, we observe that, similar to the N flux, both the Na flux and Al flux are well described by the sums of a primary cosmic ray component (proportional to the silicon flux) and a secondary cosmic ray component (proportional to the fluorine flux). The fraction of the primary component increases with rigidity for the N, Na, and Al fluxes and becomes dominant at the highest rigidities. The Na/Si and Al/Si abundance ratios at the source, 0.036±0.003 for Na/Si and 0.103±0.004 for Al/Si, are determined independent of cosmic ray propagation

Properties of Neon, Magnesium, and Silicon Primary Cosmic Rays Results from the Alpha Magnetic Spectrometer

We report the observation of new properties of primary cosmic rays, neon (Ne), magnesium (Mg), and silicon (Si), measured in the rigidity range 2.15 GV to 3.0 TV with 1.8 × 10$^{6}$ Ne, 2.2 × 10$^{6}$ Mg, and 1.6 × 10$^{6}$ Si nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The Ne and Mg spectra have identical rigidity dependence above 3.65 GV. The three spectra have identical rigidity dependence above 86.5 GV, deviate from a single power law above 200 GV, and harden in an identical way. Unexpectedly, above 86.5 GV the rigidity dependence of primary cosmic rays Ne, Mg, and Si spectra is different from the rigidity dependence of primary cosmic rays He, C, and O. This shows that the Ne, Mg, and Si and He, C, and O are two different classes of primary cosmic rays

The Alpha Magnetic Spectrometer (AMS) on the international space station: Part II — Results from the first seven years

The Alpha Magnetic Spectrometer (AMS) is a precision particle physics detector on the International Space Station (ISS) conducting a unique, long-duration mission of fundamental physics research in space. The physics objectives include the precise studies of the origin of dark matter, antimatter, and cosmic rays as well as the exploration of new phenomena. Following a 16-year period of construction and testing, and a precursor flight on the Space Shuttle, AMS was installed on the ISS on May 19, 2011. In this report we present results based on 120 billion charged cosmic ray events up to multi-TeV energies. This includes the fluxes of positrons, electrons, antiprotons, protons, and nuclei. These results provide unexpected information, which cannot be explained by the current theoretical models. The accuracy and characteristics of the data, simultaneously from many different types of cosmic rays, provide unique input to the understanding of origins, acceleration, and propagation of cosmic rays

Observation of New Properties of Secondary Cosmic Rays Lithium, Beryllium, and Boron by the Alpha Magnetic Spectrometer on the International Space Station

We report on the observation of new properties of secondary cosmic rays Li, Be, and B measured in the rigidity (momentum per unit charge) range 1.9 GV to 3.3 TV with a total of 5.4 × 106 nuclei collected by AMS during the first five years of operation aboard the International Space Station. The Li and B fluxes have an identical rigidity dependence above 7 GVand all three fluxes have an identical rigidity dependence above 30 GV with the Li=Be flux ratio of 2.0 $\pm$ 0.1. The three fluxes deviate from a single power law above 200 GV in an identical way. This behavior of secondary cosmic rays has also been observed in the AMS measurement of primary cosmic rays He, C, and O but the rigidity dependences of primary cosmic rays and of secondary cosmic rays are distinctly different. In particular, above 200 GV, the secondary cosmic rays harden more than the primary cosmic rays