Sub-acute Inhalation Exposure to Aluminum Oxide Nanoparticles and its Effects on Wistar Rats as Opposed to the Micro-sized Chemical Analog.

INTRODUCTION: Aluminum oxide nanoparticles (Al2O3 NPs) are widely used in various productions. Simultaneously, many research works report the toxic effects of this nanomaterial. Given that, there is a growing risk of negative effects produced by Al2O3 NPs on public health. AIMS: This study aims to investigate the toxic effects of Al2O3 NPs as opposed to the micro-sized chemical analogue under sub-acute inhalation exposure. MATERIALS AND METHODS: We identified the physical properties of Al2O3 NPs as opposed to the micro- sized chemical analogue, including size, specific surface area, and total pore volume. Inhalation exposure to Al2O3 NPs was simulated on Wistar rats in a chamber for whole-body. The animals were exposed for 4 hours each day for 28 days. NPs and MPs concentrations in the chamber were kept at ~ 1/4000 from LC50. Rats' behavior was examined prior to the exposure period and after it; after the last daily exposure, we examined biochemical and hematological blood indicators, NPs and MPs bioaccumulation, and pathomorphological changes in organ tissues. RESULTS: The tested Al2O3 sample is a nanomaterial according to its analyzed physical properties. Rats' behavior changed more apparently under exposure to NPs compared to MPs. Aluminum levels, which were 1.62-55.20 times higher than the control, were identified in the lungs, liver, brain, and blood under exposure to NPs. These levels were also 1.55-7.65 times higher than the control under exposure to MPs. Biochemical indicators of rats' blood also changed under exposure to NPs against the control. We identified more active ALT, AST, ALP, and LDH, elevated levels of GABA, MDA, and conjugated bilirubin, and a lower level of Glu. As opposed to exposure to MPs, ALT, AST, and ALP were more active; GABA and MDA levels were higher; Glu level was lower. Under exposure to NPs, the number of platelets grew, whereas no similar effect occurred under exposure to MPs. We established pathomorphological changes in tissues of the lungs, brain, heart, and liver under exposure to Al2O3 NPs; similar changes occurred only in the lungs under exposure to MPs. Exposure to NPs induced changes in tissue structures in a wider range of various organs, and these changes were more apparent than under exposure to MPs. CONCLUSION: Greater toxicity of Al2O3 NPs as opposed to MPs is evidenced by a wider range of organs where their bioaccumulation occurs, more apparent pathomorphological and pathological functional changes. Established peculiarities of toxic effects produced by the analyzed nanomaterial should be considered when developing hygienic recommendations aimed at preventing and mitigating adverse impacts of Al2O3 NPs on human health under inhalation exposure.

Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH.

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect risk organs (RO). The established role of the BRAF V600E mutation in LCH led to a targeted approach. However, targeted therapy cannot cure the disease, and cessation leads to quick relapses. Here, we combined cytosine-arabinoside (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 were RO-positive (RO+) and 6 RO-negative (RO-). Five patients received the therapy upfront, whereas the other 14 received it as a second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg), which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2 every 12 h, 6 mg/m2 per day, days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median disease activity score decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on day 28. All patients except 1 received complete protocol treatment, and 15 of them did not have disease progression. The 2-year reactivation/progression-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary myelodysplastic syndrome after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.

Peculiarities of bioaccumulation and toxic effects produced by nanoparticles of molybdenum (VI) oxide under multiple oral exposure of rats: examination and comparative assessment.

INTRODUCTION: Molybdenum (VI) oxide nanoparticles (MoO3 NPs) are widely used in various economic activities. This creates elevated risks of exposure to this nanomaterial for workers and population in general and, consequently, there can be an increased number of developing pathological changes caused by exposure to MoO3 NPs. OBJECTIVE: To examine and comparatively assess peculiarities of bioaccumulation and toxic effects produced by MoO NPs under multiple oral introductions. METHODS: We evaluated sizes of analyzed particles by scanning electronic microscopy; specific surface area was calculated by the method of Brunauer, Emmett and Taylor; the total pore volume, by Barrett, Joyner and Halenda. Rats were exposed as per the scheme introduced by Lim with colleagues. We examined biochemical and hematological blood indicators, molybdenum concentrations and pathomorphological changes in tissues of various organs 24 hours after the last exposure. The study involved comparison with effects produced by MoO3 microparticles. RESULTS: The tested MoO3 sample was established to be a nanomaterial as per the whole set of its physical properties. 50% of animals in the exposed group died on the 16th day in the experiment after the total exposure dose of MoO3 NPs reached 6500 mg/kg of body weight. Having analyzed blood plasma, we determined the following. There was a growth in quantity of leukocytes and a share of segmented neutrophils and monocytes, which were by 1.76-3.50 times higher than in the control group. Activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, alpha-amylase, and lactate dehydrogenase, and concentrations of urea, crude and direct bilirubin were higher by 1.61-22.86 times. Decrease in the number of platelets, plateletcrit, the relative number of lymphocytes, the number and proportion of large platelets by 1.31-2.71 times. We detected elevated molybdenum concentrations in the lungs, heart, liver, kidneys, brain and blood under exposure to MoO3 NPs in an amount exceeding the control values by 12.10-361.75 times. Rats exposed to MoO3 NPs had liver parenchymal steatosis, inflammatory changes, hemorrhagic infarctions and hyperplasia in the lungs. CONCLUSION: MoO3 NPs have a more apparent ability to bioaccumulate and produce toxic effects in comparison with their microdispersed analogue under multiple oral introductions into the body.

Vemurafenib provides a rapid and robust clinical response in pediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease per ddPCR using cell-free circulating DNA.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a disease that arises from myeloid cells that phenotypically resemble Langerhans cells (LC), which is typically driven by the BRAF V600E mutation. High-risk LCH has a poor prognosis. PROCEDURE: Fifteen children with BRAF V600E + LCH received vemurafenib between March 2016 and February 2020. The median age at LCH onset was 2 months and the median age at the start of vemurafenib treatment was 22 months. The median disease activity score (DAS) at the start of vemurafenib treatment was 12 points. RESULTS: The median duration of vemurafenib treatment was 29 months. All patients responded to treatment, with median DAS of 4 points at week 4 and 1 point at 6 months. Two patients died: 1 of hepatic failure after NSAID overdose and 1 of neutropenic sepsis. Cessation of vemurafenib resulted in relapse in 5 patients and was only possible for 1 patient. Serial measurements of BRAF V600E using cell-free circulating DNA revealed that 7 patients had persistently high mutant allele levels. CONCLUSION: Vemurafenib is effective in children with BRAF V600E + LCH. However, treatment with vemurafenib does not eradicate the disease and its long-term toxicity has not been established.

Features of Bioaccumulation and Toxic Effects of Copper (II) Oxide Nanoparticles Under Repeated Oral Exposure in Rats.

BACKGROUND: Currently, the range of copper (II) oxide nanoparticles' (CuO NPs) applications is expanding and the global production of CuO NPs is increasing. In this regard, the risk of exposure of the population to this nanomaterial is increasing. OBJECTIVE: The aim of the study is to investigate the patterns of bioaccumulation and toxic effects of CuO NPs after multiple oral exposures. METHODS: The particle size was determined by scanning electron microscopy and dynamic laser light scattering. The specific surface area was measured by the method of Brunauer, Emmett, Teller. Total pore volume - by the method of Barrett, Joyner, Khalenda. Twenty-four hours after the final exposure, blood samples were taken for biochemical and hematological analysis, and internal organs were taken to determine their mass, copper concentration and histological analysis. The study was carried out in comparison with copper (II) oxide microparticles (CuO MPs). RESULTS: In terms of size, surface area, and pore volume, the studied copper (II) oxide sample is a nanomaterial. The median lethal dose of CuO NPs was 13187.5 mg/kg of body weight. Bioaccumulation occurs in the stomach, blood, intestines, liver, lungs, kidneys and brain. Pathomorphological changes in the liver are manifested in the form of necrosis, degeneration, hepatitis; kidney - proliferation of mesangial cells, dystrophy; stomach - gastritis; small intestine - hyperplasia, enteritis; large intestine - colitis; lungs - hyperplasia, abscess, pneumonia, bronchitis, vasculitis. Clumps of brown pigment were detected in the kidneys, stomach and lungs. The mass of the stomach and intestines increased, the mass of the liver, kidneys and lungs decreased. Pathomorphological changes in organs are likely to cause an increase in the levels of activity of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, amylase, malondialdehyde concentration and a decrease in plasma antioxidant activity. The proportion of segmented neutrophils and the number of leukocytes are raised, the proportion of lymphocytes is reduced. CONCLUSION: The degree of bioaccumulation and toxicity of CuO NPs are more expressed in relation to CuO MPs.

Molecular characteristics of the Mycobacterium tuberculosis LAM-RUS family prevalent in Central Russia.

We analyzed IS6110-associated polymorphisms in the phospholipase C genes of 107 isolates of Mycobacterium tuberculosis selected to be representative of isolates circulating in central Russia. We found that the majority of Latin American-Mediterranean family strains contained an insertion in a unique position in the plcA gene, suggesting a common ancestor. This insertion can serve as a specific genetic marker for this group, which we designate the LAM-RUS family.

Predominance of multi-drug-resistant LAM and Beijing family strains among Mycobacterium tuberculosis isolates recovered from prison inmates in Tula Region, Russia.

The genotypic characteristics and drug susceptibility profiles of clinical isolates of Mycobacterium tuberculosis recovered from prison hospital patients in the Tula region (central Russia) during 2001 and 2002 are reported. The emergence of multi-drug-resistant tuberculosis (TB) poses a major health risk to the population, with economic implications for TB control. Prisons serve as a continuous source of TB transmission. The results showed that members of the LAM and Beijing families are major contributors to the epidemiological picture of TB in the population studied. The two families of strains accounted for most of the drug-resistant TB in the population. The genotypic characteristics of the M. tuberculosis predominant LAM strain that was responsible for 31 % of TB cases in this setting are presented.