Morphological Patterns of the Placenta Remodelling In Cases of IUGR at 20-25 Weeks of Gestation

Introduction/ Background Placental insufficiency is an important factor of the fetal intrauterine growth restriction (IUGR). Aims To confirm the relation between placental morphology changes and fetal IUGR 20 placentas in cases of IUGR at 20-25 weeks of gestation (wg) were compared with 20 placentas at the same wg but without fetal IUGR . Methods Material was divided: 10 placentas at 20-22wg and 10 – at 23-25wg both in cases of IUGR, which were studied with corresponding 10 (20-22wg) and 10 (23-25wg) controls. Volume fractions (vf) of the major placental components were determined from 5mmk paraffin sections. Results The results have shown that both placental and fetal weights in IUGR groups were smaller than in controls. The poor vascularisation and immaturity of the villous tree were found in cases of IUGR. The thickness of placental membrane increased from 10.74±0.09 at 20-22wg and 10.92±0.09 at 23-25wg in controls to 11.62±0.1 and 11.87±0.12mmk,

Algal and cyanobacterial lectins and their antimicrobial properties

Lectins are proteins with a remarkably high affinity and specificity for carbohydrates. Many organisms naturally produce them, including animals, plants, fungi, protists, bacteria, archaea, and viruses. The present report focuses on lectins produced by marine or freshwater organisms, in particular algae and cyanobacteria. We explore their structure, function, classification, and antimicrobial properties. Furthermore, we look at the expression of lectins in heterologous systems and the current research on the preclinical and clinical evaluation of these fascinating molecules. The further development of these molecules might positively impact human health, particularly the prevention or treatment of diseases caused by pathogens such as human immunodeficiency virus, influenza, and severe acute respiratory coronaviruses, among others.Fil: Fernández Romero, José Abel. City University of New York. The City College of New York; Estados Unidos. Center for Biomedical Research; Estados UnidosFil: Paglini, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Medicina. Instituto de Virología Dr. J. M. Vanella; ArgentinaFil: Priano, Christine. City University of New York. The City College of New York; Estados UnidosFil: Koroch, Adolfina. City University of New York. The City College of New York; Estados UnidosFil: Rodríguez, Yoel. City University of New York. The City College of New York; Estados UnidosFil: Sailer, James. Center for Biomedical Research; Estados UnidosFil: Teleshova, Natalia. Center for Biomedical Research; Estados Unido

Evaluating the Developed Model of Experimental Rhinitis in Laboratory Rats: Pre-Clinical Experimental Randomized Study

Background. Among the damaging factors affecting the mucociliary system of the nasal cavity, surgical wound is of particular relevance in the practice of an otorhinolaryngologist. The clinical assessment of regeneration of the mucociliary system is associated with certain diffi culties, since the intravital morphological examination of the nasal mucosa in patients is traumatic. Therefore, the development of animal models of experimental rhinitis is considered to be highly relevant in order to study the dynamics of mucociliary pathomorphological changes and assess the epithelium regeneration.Objectives. To evaluate the developed model of experimental rhinitis in laboratory rats by studying clinical, morphological and biochemical changes in the infl ammatory process.Methods. The experimental rhinitis model was developed and tested on 60 mature male Wistar rats. All animals were randomized into two groups: experimental group #1 (n = 30) — rats in which experimental rhinitis modeling was performed and group #2 (n = 30) — control, intact animals. In the course of the experiment, the authors examined the content of CRP in blood, evaluated the differential blood cell count, and studied a morphology of the nasal septum mucosa in 2, 5, 10 days after the injury to assess the dynamics of the infl ammatory process in rats of both groups. Statistical analysis of the study results was carried out by means of Statistica 8.0 (StatSoft Inc., USA).Results. After injury, the rats from group #1 developed acute rhinitis, which was clinically manifested by the release of mucous or mucopurulent secretion from the nostrils, sneezing and scratching the nose. An increase in CRP, band and segmented neutrophils, and a decrease in lymphocytes were observed in blood of the rats from group #1 in comparison with the control group. Microscopic analysis of changes in the nasal septum mucosa showed that the acute phase of exudative infl ammation developed on the second day: vascular congestion, edema, neutrophilic infl ammatory infi ltration of the submucosal membrane were observed against the background of foci of epithelial necrosis. The proportion of lymphocytes and macrophages in the infl ammatory infi ltrate increased by the fi fth day, initial signs of restoration of epithelial tissue — the formation of an undifferentiated regenerating epithelium — appeared by the tenth day.Conclusion. The results of the study show that an adequate experimental model of acute rhinitis in laboratory animals have been obtained. An acute infl ammatory process is characterized by clinical manifestations and changes in blood parameters. Particular destructive and reparative-proliferative changes develop in the mucous membrane of the nasal septum of experimental animals as a result of a surgical wound

In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques

The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology

The Adjuvanticity of an O. volvulus-Derived rOv-ASP-1 Protein in Mice Using Sequential Vaccinations and in Non-Human Primates

Adjuvants potentiate antigen-specific protective immune responses and can be key elements promoting vaccine effectiveness. We previously reported that the Onchocerca volvulus recombinant protein rOv-ASP-1 can induce activation and maturation of naïve human DCs and therefore could be used as an innate adjuvant to promote balanced Th1 and Th2 responses to bystander vaccine antigens in mice. With a few vaccine antigens, it also promoted a Th1-biased response based on pronounced induction of Th1-associated IgG2a and IgG2b antibody responses and the upregulated production of Th1 cytokines, including IL-2, IFN-γ, TNF-α and IL-6. However, because it is a protein, the rOv-ASP-1 adjuvant may also induce anti-self-antibodies. Therefore, it was important to verify that the host responses to self will not affect the adjuvanticity of rOv-ASP-1 when it is used in subsequent vaccinations with the same or different vaccine antigens. In this study, we have established rOv-ASP-1's adjuvanticity in mice during the course of two sequential vaccinations using two vaccine model systems: the receptor-binding domain (RBD) of SARS-CoV spike protein and a commercial influenza virus hemagglutinin (HA) vaccine comprised of three virus strains. Moreover, the adjuvanticity of rOv-ASP-1 was retained with an efficacy similar to that obtained when it was used for a first vaccination, even though a high level of anti-rOv-ASP-1 antibodies was present in the sera of mice before the administration of the second vaccine. To further demonstrate its utility as an adjuvant for human use, we also immunized non-human primates (NHPs) with RBD plus rOv-ASP-1 and showed that rOv-ASP-1 could induce high titres of functional and protective anti-RBD antibody responses in NHPs. Notably, the rOv-ASP-1 adjuvant did not induce high titer antibodies against self in NHPs. Thus, the present study provided a sound scientific foundation for future strategies in the development of this novel protein adjuvant

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population

Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option

Infants and newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB registry: a unique and challenging population

SIMPLE SUMMARY: Malignant rhabdoid tumors (MRT) are deadly tumors that predominantly affect infants and young children. Even when considering the generally young age of these patients, the treatment of infants below the age of six months represents a particular challenge due to the vulnerability of this patient population. The aim of our retrospective study was to assess the available information on prognostic factors, genetics, toxicity of treatment and long-term outcomes of MRT. We confirmed that, in a cohort of homogenously treated infants with MRT, significant predictors of outcome were female sex, localized stage, absence of a GLM and maintenance therapy, and these significantly favorably influence prognosis. Stratification-based biomarker-driven tailored trials may be a key option to improve survival rates. ABSTRACT: Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option

A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis

The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics

Герминальные нонсенс-мутации в гене SMARCB1 у российских пациентов с рабдоидными опухолями почек

The malignant rhabdoid tumor (RT) is one of the most aggressive childhood neoplasm. RTs are characterized by the presence of inactivating mutations in the SMARCB1 (hSNF5/INI1/BAF47) gene – a tumor suppressor localized in 22q11.2. Up to 30 % of RTs caused by germline mutations of this gene, to date those cases are considered as a manifestation of the rhabdoid tumor predisposition syndrome type 1 (RTPS1). We have analyzed the SMARCB1 mutations by polymerase chain reaction and subsequent Sanger sequencing in 18 patients with RT in different localizations for improving of genetic laboratory diagnostics of the RTPS1, as well as searching of genotype-phenotype correlations in this disease. Three patients had de novo nonsense-mutations c.157C→T (p.R53*), c.669_670del (p.C223*) and c.843G→A (p.W281*), confirming RTPS1, which were associated with RT in the kidney, early age at diagnosis (median 2.6 months) and poor prognosis. Identification of germline SMARCB1 mutations in the patients with RTs is essential to assess the risk of metachronous tumors and for genetic counseling of other family members.Злокачественные рабдоидные опухоли (ЗРО) относятся к одним из наиболее агрессивно протекающих новообразований раннего детского возраста. Для их развития характерно наличие инактивирующей мутации гена SMARCB1 (hSNF5/INI1/BAF47), супрессора опухолевого роста, локализованного в локусе 22q11.2. До 30% случаев заболевания обусловлено наличием герминальных мутаций этого гена, что на сегодняшний день расценивается как проявление синдрома предрасположенности к развитию рабдоидных опухолей I типа (RTPS1). С целью определения мутаций гена SMARCB1 в рамках совершенствования генетической лабораторной диагностики RTPS1, а также оценки соотношения гено-фенотипических корреляций при данном заболевании, нами было проведено исследование кодирующей части гена SMARCB1 с помощью ПЦР и последующего секвенирования у 18 пациентов с ЗРО различной локализации. У трех пациентов был подтвержден RTPS1 и найдены de novo нонсенс-мутации c.157C→T (p.R53*), с.669_670del (p.C223*) и c.843G→A (p.W281*), что ассоциировалось с ЗРО почек, ранним возрастом на момент постановки диагноза (медиана 2,6 мес) и дальнейшим неблагоприятным прогнозом заболевания. Выявление герминальных мутаций SMARCB1 у пациентов со ЗРО имеет важное значение для оценки рисков развития метахронных опухолей и медико-генетического консультирования членов семьи

Results of a phase 1, randomized, placebocontrolled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel

HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT’s preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24–45 years. In the open label period, all participants (n = 7) received single dose of PC- 6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials. gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation