Deep Immune Profiling of Multiple Myeloma at Diagnosis and under Lenalidomide Maintenance Therapy.

The bone marrow microenvironment interacts with malignant cells and regulates cancer survival and immune evasion in multiple myeloma (MM). We investigated the immune profiles of longitudinal bone marrow samples from patients with newly diagnosed MM ( = 18) using cytometry by time-of-flight. The results before and during treatment were compared between patients with good (GR, = 11) and bad (BR, = 7) responses to lenalidomide/bortezomib/dexamethasone-based treatment.

Lewis Acid-Catalyzed Formal (4+2)-Cycloaddition between Cross-Conjugated Azatrienes and Styrylmalonates: The Way to Functionalized Quinolizidine Precursors.

Quinolizidine and azaphenalene alkaloids are common in nature and exhibit a pharmaceutical activity, which stirs up increased interest in expanding the range of methods for the synthesis of the corresponding derivatives. In this work, we attempted to adapt our previously presented method for the synthesis of tetrahydropyridines to the preparation of potential precursors for these heterocycles as a separate development of a necessary intermediate stage. To this end, we studied the reactions of β-styrylmalonates with -protected cross-conjugated azatrienes in the presence of Sn(OTf).

Glucocorticoid-induced leucine zipper regulates liver fibrosis by suppressing CCL2-mediated leukocyte recruitment.

Liver fibrosis (LF) is a dangerous clinical condition with no available treatment. Inflammation plays a critical role in LF progression. Glucocorticoid-induced leucine zipper (GILZ, encoded in mice by the Tsc22d3 gene) mimics many of the anti-inflammatory effects of glucocorticoids, but its role in LF has not been directly addressed.

Patient-tailored design for selective co-inhibition of leukemic cell subpopulations.

The extensive drug resistance requires rational approaches to design personalized combinatorial treatments that exploit patient-specific therapeutic vulnerabilities to selectively target disease-driving cell subpopulations. To solve the combinatorial explosion challenge, we implemented an effective machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory acute myeloid leukemia (AML) patient cases, each with a different genetic background, we accurately predicted patient-specific combinations that not only resulted in synergistic cancer cell co-inhibition but also were capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens.

Modification of Adenosine196 by Mettl3 Methyltransferase in the 5'-External Transcribed Spacer of 47S Pre-rRNA Affects rRNA Maturation.

Ribosome biogenesis is among the founding processes in the cell. During the first stages of ribosome biogenesis, polycistronic precursor of ribosomal RNA passes complex multistage maturation after transcription. Quality control of preribosomal RNA (pre-rRNA) processing is precisely regulated by non-ribosomal proteins and structural features of pre-rRNA molecules, including modified nucleotides.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

Objective: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease.

Design: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent.

Synthesis of a New Family of 1,1-Diazidoethenes: One-Pot Construction of 4-Azido-1,2,3-triazoles via Nitrene Cyclization.

The reaction of 4,4-dichloro-1,2-diazabuta-1,3-dienes with sodium azide has been studied and found to provide straightforward access to extremely rare 1,1-bisazides. It was demonstrated that these highly unstable compounds are prone to eliminate the N molecule to cyclize into 4-azido-1,2,3-triazoles bearing two aryl (heteroaryl) groups at positions 2 and 5. The formation of bisazides was confirmed by their trapping with cyclooctyne and B3LYP calculations.

Determination of Strong Absorption Band Profiles of Low-Temperature Liquids from Reflection Spectra: The ν3 Band of Liquefied Tetrafluoromethane (CF4).

An experimental unit for recording the combined reflection-absorption spectra of low-temperature liquids was designed and manufactured and an algorithm for obtaining the extinction coefficient was developed. The manufactured experimental unit and the algorithm were tested by recording, for the first time, the absorption spectrum of liquefied CF4. The band parameters derived from the experimental data are compared with estimates available in the literature.

Prospective evaluation of malignant cell seeding after percutaneous endoscopic gastrostomy in patients with oropharyngeal/esophageal cancers.

Background And Study Aims: Insertion of a percutaneous endoscopic gastrostomy (PEG) is standard care for many patients with oropharyngeal (ENT) and esophageal malignancies in order to ensure enteral feeding. The current pull-through insertion technique involves direct contact with the tumor and case reports have demonstrated the presence of metastases at insertion sites. The aim of the current study was to prospectively evaluate the risk of malignant cell seeding and the development of abdominal wall metastases after PEG placement.

Angiotensin II AT2 receptor oligomers mediate G-protein dysfunction in an animal model of Alzheimer disease.

Progressive neurodegeneration and decline of cognitive functions are major hallmarks of Alzheimer disease (AD). Neurodegeneration in AD correlates with dysfunction of diverse signal transduction mechanisms, such as the G-protein-stimulated phosphoinositide hydrolysis mediated by Galphaq/11. We report here that impaired Galphaq/11-stimulated signaling in brains of AD patients and mice correlated with the appearance of cross-linked oligomeric angiotensin II AT2 receptors sequestering Galphaq/11.

Dominant negative AT2 receptor oligomers induce G-protein arrest and symptoms of neurodegeneration.

Neurodegeneration in Alzheimer's disease (AD) correlates with dysfunction of signaling mediated by Galphaq/11. Nondissociable angiotensin II AT2 receptor oligomers are linked to the impaired Galphaq/11-stimulated signaling of AD patients and transgenic mice with AD-like symptoms. To further analyze the role of AT2 receptor oligomers, we induced the formation of AT2 oligomers in an in vitro cell system.

Changes in glutamate decarboxylase enzyme activity and tau-protein phosphorylation in the hippocampus of old rats exposed to chronic mild stress: reversal with the neuronal nitric oxide synthase inhibitor 7-nitroindazole.

Effects of chronic stress are not completely understood. They may underlie depression and dementia. This study assessed the association between chronic stress, glutamate levels, tau-protein phosphorylation, and nitric-oxide in old rats exposed to chronic mild stress (CMS).

[A new Russian gestagen with anticancer activity].

The authors present results obtained in a complex study of 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-on (ABMP). ABMP was shown to differ from existing analogues by high gestagen activity and prolonged action. The substance does not possess androgenic or mineralocorticoid activity, is not toxic when used in high doses, and possesses significant cytostatic and chemiosensitizing activity.

[Effects of ionic and non-ionic roentgen-contrast media upon ex vivo hemostasis in rabbits].

The influence of ionic and non-ionic contrast media on the ex vivo hemostasis in rabbits was studied for ionic urografin (76 %), non-ionic ultravist-300, and non-ionic omnipaque-300 intravenously injected in medium and high doses (1.5 ml/kg and 3.0 ml/kg, respectively).

High glucose alters cardiomyocyte contacts and inhibits myofibrillar formation.

Context: The frequency of diabetes-related heart failure along with the prevalence of diabetes is increasing. Diabetic cardiomyopathy is considered to be a distinct disease in the absence of discernible coronary artery and other defined heart disease. Previously we have shown that glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in cultivated cardiomyocytes.

[Antitumor activity of the new gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one].

Antitumor activity of a new highly active promising gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (butagest) was studied in mice with model cervical carcinoma (RShM-5). The reference drug was medroxyprogesteron acetate (MPA, Depo Provera) used in clinics. The new preparation introduced perorally in a dose of 1 mg per mice inhibited the model tumor growth by 73%, which was 18% (p < 0.

[The endoscopic ligation and sclerotherapy in a complex prevention program of variceal bleedings in extrahepatic portal hypertension].

The results of prophylactic endoscopic treatment of 22 patients with extrahepatic portal hypertension (main group--EPH) and 76 patients with cirrhosis of the liver (a comparison group--CL) who had had variceal bleedings were analyzed. In the EPH group permanent eradication was obtained in 14 patients (63.6%), in the CL group--in 46 patients (50.

Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets.

High concentrations of glucose induce beta cell production of IL-1beta, leading to impaired beta cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1beta and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1beta and IL-1Ra may play a crucial role in the pathogenesis of diabetes.

Trigger-dependent gene expression profiles in cardiac preconditioning: evidence for distinct genetic programs in ischemic and anesthetic preconditioning.

Background: DNA chips facilitate genomic-wide exploration of gene expression. The authors hypothesized that ischemic (IPC) and anesthetic preconditioning (APC) would differentially modulate gene expression in hearts.

Methods: Affymetrix rat U34A gene chips were used to explore the transcriptional response to IPC and APC, sustained ischemia (110 min) without reperfusion, and time-matched perfusion in isolated rat hearts.

Combined action of doxorubicin and gestagens on doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells.

The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10(-5) M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens.

[Lowering of nephropathy risk during angiography procedure. What are choice criteria for the radiocontrast media?].

The paper analyses current data of monomer and dimmer iodine-containing radiocontrast agents used for diagnosis of cardiovascular diseases and radiovascular interventions. Considering the risk factors of nephropathy as the most common and threatening complication of radiocontrast agents the authors conclude that non-ionic monomers are the most advisable as they demonstrate optimal balance of viscosity, water solubility, osmolality and diagnostic effectiveness.