Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication

Characterizing Long COVID in Children and Adolescents

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges

THE AGGLUTINATING AND SENSITIZING CAPACITY OF ANTISERA TO SHEEP RED CELLS AFTER VARYING DEGREES OF PHOTO-OXIDATION

Tyler [1] showed that photo-oxidation could cause antisera to become nonprecipitating and nonagglutinating without destroying the ability of the antibodies to combine with the specific antigen. This was shown by the fact that treated antiserum could inhibit specifically agglutination or precipitation by corresponding untreated serum. On the basis of the mutual multivalence theory of Marrack, [2] Heidelberger, [3] and Pauling [4] it was considered that multivalent antibody had been made functionally univalent by the treatment, the term "univalent antibody" being used to designate an antibody that is incapable of causing precipitation or agglutination but which is still able to combine with the antigen. A method more sensitive and direct than that of specific inhibition for demonstrating the presence of specifically combining but nonagglutinating antibody is the antiglobulin sensitization test of Coombs, Mourant, and Race. [5] However, this method was not available when Tyler's original experiments were performed. The present experiments show that it can be used with photo-oxidized antisera, and thus one can measure more directly the sensitizing capacity of sera rendered nonagglutinating by this method. There was also a more urgent reason for undertaking the present experiments on the photo-oxidation of rabbit anti-sheep red cell sera. Coombs, Howard, and Mynors [6] reported a serological procedure theoretically capable of detecting incomplete or nonprecipitating antibodies to soluble protein antigens. The method using ox red cells, although simple in theory, is rather lengthy to perform. A much shorter method, employing sheep red cells, was envisaged if a nonagglutinating rabbit sheep cell antibody were available. [7] Tyler's work showed the possibility of producing this type of antibody by photooxidation. Chemically linked to such an antibody, a soluble protein antigen, such as egg albumin, could be fixed to the surface of sheep cells, which would nevertheless remain stable in suspension. This cell system could then be used for the specific absorption of incomplete antibody, in human serum, to the conjugated protein-the absorption being detected finally by an agglutination reaction using a rabbit anti-human globulin serum. Preliminary studies in this direction have been promising, and a shortened serological procedure for detecting incomplete antibodies to soluble protein antigens has been developed by Coombs and Fiset. [8] In the present paper various sheep cell antisera have been examined, before and after varying degrees of photo-oxidation, for their direct agglutinating action and for their combining capacity, as demonstrated by the indirect antiglobulin sensitization test

Idiotype‐Anti‐Idiotype Interactions of VHIX‐Coded Anti‐Progesterone and Anti‐Arsonate Antibodies: Comparison of Passive Haemagglutination and Radioimmunoassays

The reactivity and specificity of potyctonal and monoclonal anti‐idiotypic antibodies raised against monoclonal anti‐progesterone and anti‐arsonate antibodies have been studied by solid phase radioimmunoassay (RIA) with immobilized idiotype and by passive haemagglutination with idiotype‐coupled red cells. The sensitivity of the two methods was comparable, though some cross‐reactions were only detected by RIA. Passive haemagglutination was found to be especially suitable in screening for monoclonal anti‐idiotypes in hybridoma supernatants and ascites. and had advantages over RIA in detection of syngeneic anti‐idiotypes. Demonstration of binding site‐associated idiotopes was possible by haemagglutination inhibition. RIA and haemagglutination were used to investigate the idiotypic relationships between BALB/c antiprogesterone and anti‐arsonate monoclonal antibodies which share heavy chains encoded by VHIX variable region genes. Copyright © 1987, Wiley Blackwell. All rights reservedSCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Chikungunya virus: emerging targets and new opportunities for medicinal chemistry

Chikungunya virus is an emerging arbovirus that is widespread in tropical regions and is spreading quickly to temperate climates with recent epidemics in Africa and Asia and documented outbreaks in Europe and the Americas. It is having an increasingly major impact on humankind, with potentially life-threatening and debilitating arthritis. There is no treatment available, and only in the past 24 months have lead compounds for development as potential therapeutics been reported. This Perspective discusses the chikungunya virus as a significant, new emerging topic for medicinal chemistry, highlighting the key viral target proteins and their molecular functions that can be used in drug design, as well as the most important ongoing developments for anti-chikungunya virus research. It represents a complete picture of the current medicinal chemistry of chikungunya, supporting the development of chemotherapeutics through drug discovery and design targeting this virus