Synthesis of Tetrahydro-ß-carboline Derivatives under Electrochemical Conditions in Deep Eutectic Solvents.

In this work, a novel, green, and atom-efficient method for the synthesis of tetrahydro-ß-carboline derivatives using electrochemistry (EC) in deep eutectic solvents (DESs) was reported. The EC reaction conditions were optimized to achieve the highest yield. The experimental design was also optimized to perform the reaction in a two-step, one-pot reaction, thereby the time, workup procedure, and solvents needed were all reduced. The new approach achieved our strategy as EC served to decrease the time of reaction, eliminate the use of hazardous catalysts, and lower the energy required for the synthesis of the targeted compounds. On the other side, DESs were used as catalysts, in situ electrolytes, and noninflammable green solvents. The scope of the reaction was investigated using different aromatic aldehydes. Finally, the scalability of the reaction was investigated using a gram-scale reaction that afforded the product in an excellent yield.

Design, synthesis and in vitro anticancer activity of some new lomefloxacin derivatives.

Our main goal was to design and synthesize novel lomefloxacin derivatives that inhibit the topoisomerase II enzyme, leading to potent anticancer activity. Lomefloxacin derivatives substituted at position 3 and 7 were synthesized and screened for cytotoxic activity utilizing 60 different human cancer cell lines. Furthermore, compounds 3a,b,c,e that revealed potent broad-spectrum anticancer activity (with mean percent GI more than 47%) were further evaluated using five dose concentrations and calculating the GI50. Compound 3e was then evaluated for cell cycle analysis and demonstrated cell cycle arrest at the G2-M phase. Moreover, the mechanism of action was determined by determining the topoisomerase inhibitory activity and the molecular modeling study. Compounds 3a,b,c,e showed broad spectrum anticancer activity. Lomefloxacin derivative 5f showed selective cytotoxic activity against melanoma SK-MEL-5 cell line. Compound 3e demonstrated comparable topoisomerase II inhibition to doxorubicin with IC50 of 0.98 µM.

An initial genomic blueprint of the healthy human oesophageal microbiome.

Background: The oesophageal microbiome is thought to contribute to the pathogenesis of oesophageal cancer. However, investigations using culture and molecular barcodes have provided only a low-resolution view of this important microbial community. We therefore explored the potential of culturomics and metagenomic binning to generate a catalogue of reference genomes from the healthy human oesophageal microbiome, alongside a comparison set from saliva. Results: Twenty-two distinct colonial morphotypes from healthy oesophageal samples were genome-sequenced. These fell into twelve species clusters, eleven of which represented previously defined species. Two isolates belonged to a novel species, which we have named Rothia gullae. We performed metagenomic binning of reads generated from UK samples from this study alongside reads generated from Australian samples in a recent study. Metagenomic binning generated 136 medium or high-quality metagenome-assembled genomes (MAGs). MAGs were assigned to 56 species clusters, eight representing novel Candidatus species, which we have named Ca. Granulicatella gullae, Ca. Streptococcus gullae, Ca. Nanosynbacter quadramensis, Ca. Nanosynbacter gullae, Ca. Nanosynbacter colneyensis, Ca. Nanosynbacter norwichensis, Ca. Nanosynococcus oralis and Ca. Haemophilus gullae. Five of these novel species belong to the recently described phylum Patescibacteria . Although members of the Patescibacteria are known to inhabit the oral cavity, this is the first report of their presence in the oesophagus. Eighteen of the metagenomic species were, until recently, identified only by hard-to-remember alphanumeric placeholder designations. Here we illustrate the utility of a set of recently published arbitrary Latinate species names in providing user-friendly taxonomic labels for microbiome analyses.Our non-redundant species catalogue contained 63 species derived from cultured isolates or MAGs. Mapping revealed that these species account for around half of the sequences in the oesophageal and saliva metagenomes. Although no species was present in all oesophageal samples, 60 species occurred in at least one oesophageal metagenome from either study, with 50 identified in both cohorts. Conclusions: Recovery of genomes and discovery of new species represents an important step forward in our understanding of the oesophageal microbiome. The genes and genomes that we have released into the public domain will provide a base line for future comparative, mechanistic and intervention studies.

Acinetobacter baumannii, Klebsiella pneumoniae and Elizabethkingia miricola isolated from wastewater have biodegradable activity against fluoroquinolone.

Ciprofloxacin (CIP) and levofloxacin (LEV), widely used fluoroquinolone antibiotics, are often found in sewage from the sewage treatment plants and marine environment. In this study, CIP and LEV biodegrading bacterial consortia were obtained from industrial wastewater. Microorganisms in these consortia were identified as Acinetobacter baumannii (A. baumannii), Klebsiella pneumoniae (K. pneumoniae) and Elizabethkingia miricola (E. miricola). The impacts of the critical operating parameters on the elimination of CIP and LEV by bacterial consortia have been investigated and optimized to achieve the maximum levels of CIP and LEV biodegradation. Using liquid chromatography with tandem mass spectrometry (LC-MS-MS), possible degradation pathways for CIP and LEV were suggested by analyzing the intermediate degradation products. The role of the enzymes fluoroquinolone-acetylating aminoglycoside (6'-N-acetyltransferase) and cytochrome P450 (CYP450) in the breakdown of fluoroquinolones (FQs) was investigated as well. According to our findings, various biodegradation mechanisms have been suggested, including cleavage of piperazine ring, substitution of F atom, hydroxylation, decarboxylation, and acetylation, as the main biotransformation reactions. This study discovers the ability of non-reported bacterial strains to biodegrade both CIP and LEV as a sole carbon source, providing new insights into the biodegradation of CIP and LEV.

Development and validation of ester impregnated pH strips for locating nasogastric feeding tubes in the stomach-a multicentre prospective diagnostic performance study.

BACKGROUND: NG (nasogastric) tubes are used worldwide as a means to provide enteral nutrition. Testing the pH of tube aspirates prior to feeding is commonly used to verify tube location before feeding or medication. A pH at or lower than 5.5 was taken as evidence for stomach intubation. However, the existing standard pH strips lack sensitivity, especially in patients receiving feeding and antacids medication. We developed and validated a first-generation ester-impregnated pH strip test to improve the accuracy towards gastric placements in adult population receiving routine NG-tube feeding. The sensitivity was improved by its augmentation with the action of human gastric lipase (HGL), an enzyme specific to the stomach. METHODS: We carried out a multi-centred, prospective, two-gate diagnostic accuracy study on patients who require routine NG-tube feeding in 10 NHS hospitals comparing the sensitivity of the novel pH strip to the standard pH test, using either chest X-rays or, in its absence, clinical observation of the absence of adverse events as the reference standard. We also tested the novel pH strips in lung aspirates from patients undergoing oesophageal cancer surgeries using visual inspection as the reference standard. We simulated health economics using a decision analytic model and carried out adoption studies to understand its route to commercialisation. The primary end point is the sensitivity of novel and standard pH tests at the recommended pH cut-off of 5.5. RESULTS: A total of 6400 ester-impregnated pH strips were prepared based on an ISO13485 quality management system. A total of 376 gastric samples were collected from adult patients in 10 NHS hospitals who were receiving routine NG-tube feeding. The sensitivities of the standard and novel pH tests were respectively 49.2% (95% CI 44.1­54.3%) and 70.2% (95% CI 65.6­74.8%) under pH cut-off of 5.5 and the novel test has a lung specificity of 89.5% (95% CI 79.6%, 99.4%). Our simulation showed that using the novel test can potentially save 132 unnecessary chest X-rays per check per every 1000 eligible patients, or direct savings of £4034 to the NHS. CONCLUSIONS: The novel pH test correctly identified significantly more patients with tubes located inside the stomach compared to the standard pH test used widely by the NHS. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN11170249 , Registered 21 June 2017-retrospectively registered.

Impact of Change in Lifestyle and Exercise on Cognitive Function in Patients With Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is a chronic destructive type of arthritis. It has a high prevalence in females as compared to the male population globally. It mainly affects the synovium of peripheral joints and leads to the destruction of joints with time. Patients with RA usually have a high burden of inflammation which may lead to certain physical disabilities and debilitating effects on mental health and cognitive ability. The question we investigated here in this systematic review is how changing lifestyles and increasing exercise or physical activities affects one's cognitive abilities. This article adheres to preferred reporting items for systematic review and meta-analyses (PRISMA) guidelines. We used different databases such as PubMed, MEDLINE, and ScienceDirect to find relevant articles. To ensure the quality of the finally selected 12 studies, we followed different quality appraisal tools.  Based on our review, we found out that increasing physical activities and aerobic exercises positively increase overall well-being and decrease the inflammatory load, which will ultimately positively impact cognitive function in this subgroup of patients. We also discover certain key players affecting motivation, perception, and adherence to physical activities. We encourage future studies to be done on this topic to help in increasing quality of life and increasing independence in this group of patients. Counseling and addressing patient concerns are very important and keep disease activity well controlled so that physical activities become feasible.

The Effect of Statin Therapy on Inflammatory Biomarkers: A Systematic Review.

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors are commonly used drugs in the management of elevated lipid levels and cardiovascular disease. In cardiovascular diseases, among other common chronic conditions, inflammatory biomarkers are used to monitor disease progression and the risk of recurrent adverse events. We explored whether or not there was a positive effect on these biomarkers using HMG-CoA reductase inhibitors. The systematic review was conducted by gathering relevant papers mainly from three databases, identified through a generated Medical Subject Headings (MeSH) strategy. Identification of papers was subsequently followed by applying a selected inclusion and exclusion criteria to narrow the papers chosen for review. Post the application of stipulated criteria, 12 papers remained. They were subsequently assessed for risk of bias using a Cochrane risk analysis tool, identifying most as having some concerns of bias or low risk of bias. We found that HMG-CoA reductase inhibitors exhibit both a lipid-lowering effect addition to an anti-inflammatory effect.

Cardiovascular Benefit of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Type 2 Diabetes: A Systematic Review.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide yet, despite advances in treatment, CVD remains an underestimated and undermanaged condition, with an even greater risk in Type 2 Diabetes Mellitus (T2DM). Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are a promising novel drug class reported to improve Cardiovascular (CV) and renal outcomes in T2DM. Recent large-scale trials have assessed their CV safety with unexpected findings of multiple systemic benefits that could potentially reverse CVD. In this systematic review, we examined ten Randomized Controlled Trials (RCTs) that looked at cardiovascular outcomes in Type 2 diabetics and SGLT-2i. The RCTs were appropriately screened, looking for clear primary or secondary outcomes on CV events, and compared with placebo or other antidiabetic drugs. The RCTs had an average sample population studied of 5,549 participants with a mean follow-up time of 2.66 years. Three of the studies focused on CV parameters and risk factors. The remaining had defined CV composite events, and all consistently observed at least one CV benefit when using SGLT-2i. Our review of SGLT-2i in Type 2 diabetics showed the greatest benefit in reducing Heart Failure (HF) exacerbation and modest lowering of CV complications in high CV risk participants. Overall, there is still uncertainty about the exact mechanisms of SGLT-2i in their CV benefit, and whether they would favor pre-diabetic populations and those at earlier stages of CVD.

Understanding the Genetic and Molecular Basis of Familial Hypertrophic Cardiomyopathy and the Current Trends in Gene Therapy for Its Management.

Hypertrophic cardiomyopathy (HCM) is a genetically acquired disease of cardiac myocytes. Studies show that 70% of this disease is a result of different mutations in various sarcomere genes. This review aims to discuss several genetic mutations, epigenetic factors, and signal transduction pathways leading to the development of HCM. In addition, this article elaborates on recent advances in gene therapies and their implications for managing this condition. We start by discussing the founding mutations in HCM and their effect on power stroke generation. The less explored field of epigenetics including methylation, acetylation, and the role of different micro RNAs in the development of cardiac muscle hypertrophy has been highlighted in this article. The signal transduction pathways that lead to gene transcription, which in turn lead to increased protein synthesis of cardiac muscle fibers are elaborated. Finally, the microscopic events leading to the pathophysiologic macro events of cardiac failure, and the current experimental trials of gene therapy models, and the clustered regularly interspaced short palindromic repeats (CRISPR) type 2 system proteins, are discussed. We have concluded our discussion by emphasizing the need for more studies on epigenomics and experimental designs for gene therapy in HCM patients. This review focuses on the process of HCM from initial mutation to the development of phenotypic expression and various points of intervention in cardiac myocardial hypertrophy development.

Diagnostic Pitfalls of Digital Microscopy Versus Light Microscopy in Gastrointestinal Pathology: A Systematic Review.

Digital microscopy (DM) is one of the cutting-edge advances in pathology, which entails improved efficiency, diagnostic advantages, and potential application in virtual diagnosis, particularly in the current era of the coronavirus disease (COVID-19) pandemic. However, the diagnostic challenges are the remaining concerns for its wider adoption by pathologists, and these concerns should be addressed in a specific subspecialty. We aim to identify the common diagnostic pitfalls of whole slide imaging (WSI), one modality of DM, in gastrointestinal (GI) pathology. From validating studies of primary diagnosis performance, we included 16 records with features on GI cases involved, at least two weeks wash-out periods, and more than 60 case study designs. A tailored quality appraisal assessment was utilized to evaluate the risks of bias for these diagnostic accuracy studies. Furthermore, due to the highly heterogeneous studies and unstandardized definition of discordance, we extract the discordant cases in GI pathology and calculate the discrepant rate, resulting from 0.5% to 64.28%. Targeting discrepancy cases between digital microscopy and light microscopy, we demonstrate five main diagnostic pitfalls regarding WSI as follows: additional time to review slides in WSI, hard to identify dysplasia nucleus, missed organisms like Helicobacter pylori (H. pylori), specific cell recognitions, and technical issues. After detailed reviews and analysis, we generate two essential suggestions for further GI cases signing out by DM. One is to use systematized 20x scans for diagnostic workouts and requesting 40x or even 60x scans for challenging cases; another is that a high-volume slides training should be set before the real clinical application of WSI for primary diagnosis, particularly in GI pathology.

Modulation of immune functions, inflammatory response, and cytokine production following long-term oral exposure to three food additives; thiabendazole, monosodium glutamate, and brilliant blue in rats.

The food additives thiabendazole (TBZ), monosodium glutamate (MSG), and brilliant blue (BB) are commonly used in many daily-consumed food products worldwide. They are widely used in major agricultural and industrial applications. Yet, many of its toxicological aspects are still unclear, especially immune modulation. This research was therefore intended to investigate the effects of male Wistar rats' daily oral exposure for 90 days to TBZ (10 mg/kg b.wt), MSG (20 mg/kg b.wt), or BB (1.2 mg/kg b.wt) on the blood cells, immunity, and inflammatory indicators. The three tested food additives showed varying degrees of hematological alterations. Initially, megaloblastic anemia and thrombocytopenia were evident with the three tested food additives. At the same time, TBZ showed no significant changes in the leukogram element except eosinopenia. MSG induced leukopenia, lymphocytopenia, neutrophilia, and eosinophilia. BB evoked neutrophilia and lymphopenia. The immunoglobins M (IgM) and IgG were significantly reduced with the three tested food additives. In contrast, lysozyme and nitric oxide levels were elevated. A reduced considerably lymphocyte proliferation was detected with TBZ and MSG exposure without affecting the phagocytic activity. Various pathologic disturbances in splenic tissues have been detected. An obvious increase in CD4+ but a lessening in CD8+ immunolabeling was evident in TBZ and MSG groups. The cytokines, including interferon-gamma, tumor necrosis factor-alpha, and interleukin 1ß, 6, 10, and 13, were significantly upregulated in the spleen of rats exposed to TBZ, MSG, and BB. These results concluded that TBZ, MSG, and BB negatively affect hematological parameters, innate and humoral immune functions together with inflammatory responses. TBZ achieved the maximal negative impacts followed by MSG and finally with BB. Given the prevalence of these food additives, TBZ and MSG should be limited to a minimal volume use, or natural food additives should be used instead.

[The food habits of women as a factor of development of maternal obesity].

The article presents the results of analysis of diet habits of women in the Stavropol Krai. The study was carried out using single-stage structured interview quantitative survey. The respondent was guaranteed anonymity and the purpose of survey was explained. The questionnaire was targeted to identify diet habits of respondents and to establish their dependence with place of residence, infant feeding schedule, body mass index. The statistical data processing was performed using SPSS v. 24 software. The study demonstrated that majority of respondents feed in a fractional and varied way. The population often pays attention to the storage life of products while buying them. But only 12.5% respondents always control the caloric content of food. The obese women are more attentive to the energy value of food (pm0.001), as well as women feeding infant in a natural way (p=0.002). The respondents consume sweets and regularly add sugar to their drinks. Almost half of women assume that they need to lose weight and 37% tried to lose weight through dieting and 30% of respondents used various medications for weight loss. At that, only 21.2% of respondents were able to achieve the desired weight.

Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma.

Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients' breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis.

Functional Activity of Lymphocytes of Healthy Donors and Cancer Patients After Culturing with IL-2 and IL-15.

The study focused on activation of lymphocytes derived from healthy donors and cancer patients in the medium supplemented with IL-2 and IL-15 at low concentrations. We studied morphological features of cultured cells, their viability, and proliferative and functional activities during culturing for up to 14 days. In comparison with lymphocytes derived from cancer patients, white blood cells derived from healthy donors demonstrated a number of advantages under the given culturing conditions such as higher viability, greater proliferative activity, and the potency for earlier activation; moreover, during activation they secreted the anti-inflammatory cytokines IL-4 and IL-10 at greater concentrations.

Mass-Spectrometry Analysis of Mixed-Breath, Isolated-Bronchial-Breath, and Gastric-Endoluminal-Air Volatile Fatty Acids in Esophagogastric Cancer.

A noninvasive breath test has the potential to improve survival from esophagogastric cancer by facilitating earlier detection. This study aimed to investigate the production of target volatile fatty acids (VFAs) in esophagogastric cancer through analysis of the ex vivo headspace above underivatized tissues and in vivo analysis within defined anatomical compartments, including analysis of mixed breath, isolated bronchial breath, and gastric-endoluminal air. VFAs were measured by PTR-ToF-MS and GC-MS. Levels of VFAs (acetic, butyric, pentanoic, and hexanoic acids) and acetone were elevated in ex vivo experiments in the headspace above esophagogastric cancer compared with the levels in samples from control subjects with morphologically normal and benign conditions of the upper gastrointestinal tract. In 25 patients with esophagogastric cancer and 20 control subjects, receiver-operating-characteristic analysis for the cancer-specific VFAs butyric acid ( P < 0.001) and pentatonic acid ( P = 0.005) within in vivo gastric-endoluminal air gave an area under the curve of 0.80 (95% confidence interval of 0.65 to 0.93, P = 0.01). Compared with mixed- and bronchial-breath samples, all examined VFAs were found in highest concentrations within esophagogastric-endoluminal air. In addition, VFAs were higher in all samples derived from cancer patients compared with in the controls. Equivalence of VFA levels within the mixed and bronchial breath of cancer patients suggests that their origin within breath is principally derived from the lungs and, by inference, from the systemic circulation as opposed to direct passage from the upper gastrointestinal tract. These findings highlight the potential to utilize VFAs for endoluminal-gas biopsies and noninvasive mixed-exhaled-breath testing for esophagogastric-cancer detection.

Novel nalidixic acid derivatives targeting topoisomerase II enzyme; Design, synthesis, anticancer activity and effect on cell cycle profile.

AIM: Design and synthesis of novel nalidixic acid derivatives of potent anticancer and topoisomerase II inhibitory activities were our major aim. MATERIALS & METHODS: All the newly synthesized nalidixic acid derivatives were submitted to the National Cancer Institute (NCI), Bethesda, USA and were accepted for single dose screening. Further investigation via IC50 determination of the most potent compound 6a against K-562 and SR leukemia cell lines. Finally, the topoisomerase II inhibitory activity, the cell cycle analysis and molecular docking of 6a were performed in order to identify the possible mechanism of the anticancer activity. RESULTS: Compound 6a showed interesting selectivity against leukemia especially K-562 and SR subpanels with IC50 35.29 µM and 13.85 µM respectively. Moreover, compound 6a revealed potent topoisomerase IIα and topoisomerase IIß inhibitory activity compared with known topoisomerase inhibitors such as doxorubicin and topotecan with IC50 1.30 µM and 0.017 µM respectively. Cell cycle analysis indicated that compound 6a induced cell cycle arrest at G2-M phase leading to inhibition of cell proliferation and apoptosis. Molecular modeling demonstrated that the potent topoisomerase inhibitory activity of 6a was due to the interaction with the topoisomerase II enzyme through coordinate bonding with the magnesium ion Mg2+, hydrogen bonding with Asp 545 and arene cation interaction with His 759.

Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity.

BACKGROUND: 4-Substitutedaminoquinazoline scaffolds were reported to possess potent cytotoxic and EGFR inhibitory activity such as gefitinib (Iressa), erlotinib (Tarceva) and tandutinib. OBJECTIVE: Synthesis of novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives as bioisosters of 4-substitutedaminoquinazoline derivatives with potential cytotoxic and EGFR inhibitory activity. METHODS: Novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives 4a-i and 5a-c were synthesized via reacting corresponding 4-chlorothieno[2,3-d]pyrimidine derivatives 3a-c with N-methylpiperazine, morpholine, N-phenylpiperazine or 1,3-propanediamine. Six compounds (2a, 4d, 4e, 5a-c) were selected by the National Cancer Institute (USA) for evaluating their cytotoxic activity using 60 different human tumor cell lines using a single dose (10-5 Molar). The rest of the synthesized compounds (2b, 2c, 3a-c, 4a-c and 4f-i) were subjected to screening against T47D breast cancer cell line using a single dose (10-5 Molar) at Pharmacology lab., Cancer biology lab., Egyptian National Institute. Moreover, compounds 2a and 4b-e were subjected to further evaluation by IC50 determination. Finally, the inhibition of epidermal growth factor receptor (EGFR) was then investigated for the most active compounds 2a and 4d. RESULTS: Compounds 2a and 4b-e showed significant cytotoxic activity. Compound 2a was more potent than doxorubicin against lung cancer cell line A549 with IC50 = 13.40 µM and comparable activity against MCF7. Compound 4d exhibited more potent activity than Doxorubicin against prostate PC3 (IC50 = 14.13 µM) while showed comparable activity against MCF7 and T47D. CONCLUSION: 4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads.

HDAC Inhibitors.

Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment.

[Implementation of systemic approach to evaluation of carcinogenic jeopardy, exemplified by copper metallurgy].

The authors suggested scientific and methodic approaches based on hygienic and medical prophylactic technologies to define carcinogenically dangerous occupations with unacceptable level of occupational carcinogenous risk, to control oncogenesis predictors in these occupations, to diagnose early stages of oncologic diseases, to specify medical and prophylactic measures -aimed to decrease oncologic morbidity.

[HYGIENIC DIAGNOSIS--A KEY ELEMENT IN THE HEALTH-PREVENTION TECHNOLOGIES FOR THE POPULATION RESIDING IN CONDITIONS OF HIGHER CHEMICAL LOAD].

This article is devoted to the review of methods and technologies of hygienic diagnostics implemented in the frameworks of the regional system of socio-hygienic monitoring for the Sverdlovsk Region for the purposes of the management ofthe quality ofenvironment and the state ofthe population's health. Under conditions of impossibility to take immediate performance of radical technological and technical measures mitigating adverse effects of industries and road transport on the living environment and due to limitation of financial expenses, the proposed algorithm of actions helps to establish priority factors, environmental objects, and routes ofexposure, evaluate predicted values of a multiple environmental assessment of health risk, specify dose-response relations in environmental epidemiological studies, substantiate the choice of the most susceptible groups of population, for which the implementation of targeted rehabilitation gives the significant medical and economic efficiency.