Methylenebisphosphonates with dienone pharmacophore: synthesis, structure, antitumor and fluorescent properties

The synthesis and the antitumor activity and fluorescent properties screening of novel bisphosphonate conjugates with cytotoxic 3,5‐bis((hetero)arylidene)‐4‐piperidone residues were performed. The facile and rapid synthetic route was based on the aza‐Michael addition of NH‐3,5‐bis((hetero)arylidene)‐4‐piperidones to tetraethyl ethylidenebisphosphonate. The synthesized compounds displayed high inhibitory properties towards Caov3, A549, PC3, and KB 3‐1 human carcinoma cell lines. Among those, compounds bearing 4‐cyano‐phenyl and 3‐pyridinyl substituents were revealed as the most active drug candidates with IC₅₀ values in the range of 0.5–2.5 µM. Methylenebisphosphonate with 4‐Me₂N‐C₆H₄ groups in the piperidone framework possessing fluorescence properties may be of interest for visualization of BPs skeletal distribution and cellular uptake in bones and other tissues.     

Evaluation of a serum 17-hydroxyprogesterone as a predictor of semen parameter improvement in men undergoing medical treatment for infertility

IntroductionThe goal of medical therapy for infertile men with testosterone deficiency (TD) is to improve intratesticular testosterone (ITT). There is a gap in knowledge to identify those who will respond with semen parameter(s) improvement. We hypothesized that serum 17-hydroxyprogesterone (17-OHP) — a marker of ITT — can be used to predict improvement of semen parameter(s).MethodsBetween July 2018 and January 2020, we conducted a prospective study of 31 men with primary infertility, TD, and secondary hypogonadism receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG) for three months. We assessed baseline and followup hormones, including testosterone, 17-OHP, semen parameter(s), and demographics. Semen quality upgrading was based on assisted reproduction eligibility: in-vitro fertilization (<5 million), intrauterine insemination (IUI) (5–9 million), and natural pregnancy (>9 million). Variables were compared using the Mann-Whitney U or Wilcoxon rank test.ResultsTwenty-one men received CC and 10 received CC/hCG. Median followup was 3.7 (3.3–5.1) months. Sixteen men upgraded semen quality. Six of 10 men with baseline total motile sperm count (TMSC) of 0 had motile sperm after treatment, and 11/20 men with TMSC <5 upgraded semen quality into TMSC >5 range. Low 17-OHP was the only factor that predicted semen quality upgrading. Men with 17-OHP ≤55 ng/dL upgraded semen quality and improved hormones, whereas men with 17-OHP >55 ng/dL did not upgrade semen quality.ConclusionsMedical therapy for infertile men with TD resulted in the improvement of sperm concentration, TMSC, testosterone, and 17-OHP. Semen quality upgrading appears to be more significant in patients with low 17-OHP, suggesting that ITT can be used as a biomarker to predict semen parameter(s) improvement.     

'Comparison of extremes' approach provides evidence against the modifying role of NAT2 polymorphism in lung cancer susceptibility

NAT2 (arylamine N-acetyltransferase 2) polymorphism, being a key determinant of individual variations in acetylation capacity, is suspected to modify the risk of carcinogen-related malignancies. As tobacco smoke and other inhaled hazards contain a variety of NAT2 substrates, the relationship between NAT2 phenotype and lung cancer (LC) risk has been a subject of intensive research, however different case-control studies produced controversial data. In the present report, we employed a novel 'comparison of extremes' approach, i.e. we compared the distribution of NAT2 genotypes in lung cancer patients (LC, n=178) not only to the population controls (healthy donors (HD), n=364), but also to the subjects with a putative cancer-resistant constitution (elderly tumor-free smokers and non-smokers (ED), n=351). Frequencies of homozygous rapid, heterozygous rapid and slow acetylators were 6, 39 and 56% in LC, 8, 32 and 60% in HD, and 6, 35 and 59% in ED, respectively. Comparison of the NAT2 genotype frequencies between affected and non-affected individuals did not reveal any statistical deviations, irrespectively of smoking history, gender, age, or histological type of LC. Adjusted odds ratio for rapid vs. slow acetylators was 1.12 (95% confidence intervals (CI): 0.73-1.74) comparing LC vs. HD, and 1.10 (95% CI: 0.74-1.62) comparing LC vs. ED. Similar distribution of NAT2 acetylator genotypes both in tumor-prone and in tumor-resistant groups suggests that, despite the presence of NAT2 carcinogenic substrates in tobacco smoke, NAT2 polymorphism does not play a noticeable role in lung cancer susceptibility.     

Circulating antibodies to human spermatozoa in patients with ulcerative colitis

The existence of enhanced humoral immunity against sperm antigens in patients with ulcerative colitis might be a result of the increased intestinal permeability, and may be associated with immunization against antigens of the common intestinal flora possessing common antigenicity with spermatozoa. The result of these two processes is statistically significant increased antisperm antibody (ASA) incidence in patients with ulcerative colitis compared to the healthy blood donors of proven fertility without clinical symptoms of inflammatory bowel diseases at the same age.     

Risk of various types of cataracts in a cohort of Mayak workers following chronic occupational exposure to ionizing radiation

This study is the first to report cataract type specific risks in a cohort of Russian Mayak Production Association workers following chronic occupational exposure to ionizing radiation. In this retrospective cohort study, 22,377 workers (females 25.4%) first employed in 1948–1982 were followed up till the end of 2008. All cataract subtypes were significantly dependent on sex, attained age, diabetes mellitus, myopia and glaucoma. For each of posterior subcapsular (PSC), cortical and nuclear cataracts, the risk of cataract incidence significantly linearly increased with increasing radiation dose. Excess relative risk per unit effective dose (ERR/Sv) from external γ-rays based on the linear model was 0.91 [95% confidence intervals (CIs) 0.67, 1.20] for PSC, 0.63 (95% CIs 0.49, 0.76) for cortical, and 0.47 (95% CIs 0.35, 0.60) for nuclear cataracts. For all three types of cataracts, exclusion of an adjustment for neutron dose as well as inclusion of additional adjustments for body mass index and smoking index decreased ERR/Sv of external γ-rays. Inclusion of an additional adjustment for glaucoma, however, modestly increased incidence risks for cortical and nuclear cataracts, but not PSC cataracts. Inclusion of an adjustment for diabetes mellitus decreased ERR/Sv of external γ-rays only for PSC incidence. Both males and females had increased risks for all three types of cataracts, but ERR/Sv was significantly higher in females than in males (p?<?0.001), particularly for PSC cataracts. The results suggest that chronic occupational radiation exposure significantly increases risks of PSC, cortical and nuclear cataracts, and that such risks are higher in females than in males.     

TULA proteins bind to ABCE-1, a host factor of HIV-1 assembly, and inhibit HIV-1 biogenesis in a UBA-dependent fashion

TULA, a recently identified UBA- and SH3-containing protein, has previously been shown to regulate cell signaling through protein tyrosine kinases. In order to search for novel functions of TULA, we identified, using mass spectrometry, proteins associated with TULA. ABCE-1 also known as RLI and HP68, a host factor of HIV-1 assembly, was found among TULA-associated proteins in these experiments. Considering an important role of ABCE-1 in HIV-1 assembly, we were compelled to analyze the effect of TULA on HIV-1 biogenesis. Our study provides evidence that TULA proteins substantially inhibit production of both sub-genomic and full-length HIV-1 viral particles and that the effect of TULA is dependent on UBA domain-mediated interactions. The primary role of ABCE-1 in the effect of TULA appears to be the recruitment of TULA to the sites of HIV-1 assembly where TULA interferes with the late steps of the HIV-1 life cycle, most likely by disrupting essential ubiquitylation-dependent events that remain to be identified.     

High Strength Al–La,Al–Ce,and Al–Ni Eutectic Aluminum Alloys Obtained by High-Pressure Torsion

A comparative analysis of the effect of high-pressure torsion (HPT) on the microstructure and tensile properties of the Al–10% La, Al–9% Ce, and Al–7% Ni model binary eutectic aluminum alloys is carried out. An HPT of 20-mm diameter specimens in as-cast state was carried out under constrained conditions, at room temperature, pressure P = 6 GPa, and number of turns N = 5. It is shown that the formation of nano- and submicrocrystalline structures and the refinement of eutectic particles in aluminum alloys simultaneously provide a multiple increase in strength while maintaining a high plasticity margin. This combination of properties has been achieved for the first time for severely deformed binary aluminum eutectics. The relationship between the type of eutectic particles, the structure formation process and the mechanical properties of the aluminum alloys has been established. The thermal stability of severely deformed aluminum alloys at heating up to 200 °C has been studied.     

Efficacy of the new therapeutic approach in curing malignant neoplasms on the model of human glioblastoma

Objective:Glioma is a highly invasive tumor, frequently disposed in essential areas of the brain, which makes its surgical excision extremely difficult; meanwhile adjuvant therapy remains quite ineffective.Methods:In the current report, a new therapeutic approach in curing malignant neoplasms has been performed on the U87 human glioblastoma model. This approach, termed “Karanahan”, is aimed at the eradication of cancer stem cells (CSCs), which were recently shown to be capable of internalizing fragments of extracellular double-stranded DNA. After being internalized, these fragments interfere in the process of repairing interstrand cross-links caused by exposure to appropriate cytostatics, and such an interference results either in elimination of CSCs or in the loss of their tumorigenic potency. Implementation of the approach requires a scheduled administration of cytostatic and complex composite double-stranded DNA preparation.Results:U87 cells treated in vitro in accordance with the Karanahan approach completely lost their tumorigenicity and produced no grafts upon intracerebral transplantation into immunodeficient mice. In SCID mice with developed subcutaneous grafts, the treatment resulted in reliable slowing down of tumor growth rate (P < 0.05). In the experiment with intracerebral transplantation of U87 cells followed by surgical excision of the developed graft and subsequent therapeutic treatment, the Karanahan approach was shown to reliably slow down the tumor growth rate and increase the median survival of the mice twofold relative to the control.Conclusions:The effectiveness of the Karanahan approach has been demonstrated both in vitro and in vivo in treating developed subcutaneous grafts as well as orthotopic grafts after surgical excision of the tumor.