Evolution of a Synthetic Strategy for Complex Polypyrrole Alkaloids: Total Syntheses of Curvulamine and Curindolizine.

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C10N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.

Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling.

Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone-derived ß-lactone as the key intermediate that was transformed into a δ-lactone appended to the D-ring of the steroidal scaffold. This natural-product-inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase-independent manner.

Biology-oriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling.

Biology-oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans-hydrindane dehydro-δ-lactone motif defines the characteristic scaffold of the steroid-like withanolides, a plant-derived natural product class with a diverse pattern of bioactivity. A withanolide-inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell-based assays that monitored biological signal-transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened.

Outcomes of laser-induced thermotherapy for thyroid nodules at the West Vascular Center, Ukraine.

Thyroid nodules are common, occurring in 50-60% of healthy patients. Currently, there are no effective conservative treatment options for nodular goiter, and surgery can have limitations and potential complications. The purpose of this study was to evaluate the efficacy, tolerability, and long-term results of using sclerotherapy and laser-induced interstitial thermotherapy (LITT) to treat benign thyroid nodules. A retrospective analysis was conducted on 456 patients with benign nodular goiter who received LITT. The volume of the nodular goiter was measured at 1, 3, 6, and 12 months post-treatment, and a repeated fine needle aspiration (FNA) with the cytological examination was performed to verify the structure of the nodular goiter in the long term. The results showed that LITT was an effective method for treating nodular mass (nodules), as evidenced by a decrease in the volume of NG by 51-85% after 6-12 months. FNA results 2-3 years after LITT showed no thyrocytes, only connective tissue, indicating the efficacy of LITT for benign thyroid nodules. LITT is highly effective in most cases, often resulting in the disappearance or significant decrease in nodular formations.

Features of VEGF and IL-6 expression in patients with inflammatory breast cancer considering molecular-biological characteristics.

Expression of pro-malignant factors (VEGF) and cytokines like inflammatory components support breast cancer development. We examined 46 patients with stage IIIB inflammatory breast cancer (IBC) and 24 with stage IIA-IIIB breast cancer (BC) without secondary edema. Hormone receptors, Her-2/neu, Ki-67 index, VEGF, and IL-6, were determined for all patients before and after neoadjuvant treatment. They associated the expression of VEGF for IBC patients with an unfavorable prognosis. VEGF level for IBC lymph node metastases was higher than in patients without such lesions (1.4 times), and there was a significant increase in VEGF levels in the G3 category of malignancy (1.54-fold increase). In IBC patients with positive HER2/neu status, VEGF levels were 1.51 times higher compared to those with negative HER2/neu status (r=0.36, p<0.05). IL-6 level during therapy in IBC patients remained high, which occurs in active tumor development. Comparative analysis of the VEGF/IL-6 ratio during treatment of patients with IBC was higher vs. IIIB stage breast cancer without edema (1.4 vs. 0.7), indicating the aggressiveness of the tumor process and confirmed by an objective response to treatment (regression<30%).

Main factors determining the use of free MS-TRAM and DIEP flaps and comparing the results of breast reconstruction.

This study aimed to compare the results of free MS-TRAM and DIEP-flap based on the volume of the transplant and the unique characteristics of blood flow in the tissues. The study included 83 patients, 42 in the MS-TRAM-flap reconstruction group and 41 in the DIEP-flap breast reconstruction group. In the MS-TRAM-flap group, 35 patients received delayed reconstruction, and 7 received one-stage breast reconstruction, including one case of bilateral transplantation. In the DIEP-flap group, 5 patients received one-stage reconstruction, and 36 received delayed reconstruction. Complications associated with the flap tissue were observed in 7 (16.67%) in the MS-TRAM-flap group and 8 (19.51%) cases in the DIEP-flap group. The total level of fat necrosis in MS-TRAM-flap was 7.14% (p=0.033), and in DIEP-flap, it was 9.75% (p=0.039) (2 patients had a substantial amount of fat necrosis, while 2 patients had a modest amount of focal fat necrosis). The number and diameter of perforators (including veins), as well as the transplant volume, are the primary determinants of whether to use a DIEP- or MS-TRAM-flap. DIEP-flap is preferred if there are 1-2 large artery perforators (≥1 mm) and tissue volume of 700-800 grams, while MS-TRAM-flap is used when the tissue volume is significant (>2/3 of standard TRAM-flap).

Breast cancer relapses considering molecular biological characteristics.

We aimed to analyze the frequency of breast cancer relapses and their relationship with molecular and biological tumor characteristics. We studied 6,136 breast cancer patients, including 146 with relapses (Group 1) and 455 without relapses (Group 2). We divided the patients based on age, menstrual function, disease stage, histology form and grade, and molecular-biological subtype. The 5-year relapse-free rate for Group 1 was longer for Lum A and TN subtypes (60% and 40%, respectively) but shorter for Lum B and HER-2/neu-amplified subtypes (38% and 31%, respectively). Disease stage, tumor histology, and grade did not significantly affect relapse frequency in these patients. Relapses were more common in premenopausal patients and the Lum B subtype.

Ontogenetic variations of proteins in neurons of the lateral preoptic nucleus of rats' hypothalamus under a modified light regime.

Proteins can be key biochemical markers for evaluating the functional activity of nervous system cells. They are involved in the proliferation and differentiation of nerve and glial cells and the arrangement of many metabolic functions of the brain. This study aimed to analyze the concentration of proteins in the neurons of the lateral preoptic nucleus (LPON) of the hypothalamus in mature and old rats under standard and altered lighting conditions. Our results show that the concentration of proteins in mature rats was significantly higher than in old rats (0.274±0.0017 optical density units), with a predominance of carboxyl groups, indicating a high intensity of protein metabolism. Additionally, we found that changes in the lighting regime have a differential effect on the optical density of specific staining for protein in LPON neurons. Specifically, light deprivation did not significantly alter the optical density of specific staining for protein in neurons of the hypothalamus LPON of mature rats regardless of the period of the day, while in old rats, the intensity of protein staining decreased. Light exposure, on the other hand, led to an increase in the average color intensity for protein in neurons of the hypothalamus LPON in mature rats (0.326±0.0014 optical density units), while in old rats, a decrease in the average color intensity for protein in neurons of the hypothalamus LPON was observed (0.196±0.0017 optical density units).

The outcomes of a methodology for developing prospective pharmacists' English lexical competence.

This study assessed the effectiveness of a methodology aimed at developing prospective pharmacists' professionally oriented English lexical competence in reading and speaking during individual study. The methodology considered students' interests and experience, forming lexical skills in reading, speaking, listening, and writing, integration with professional subjects, learning metacognitive, cognitive, and compensatory strategies, enhancing students' autonomy through purposeful forming their reflexive abilities, developing professionally oriented English lexical competence in reading and speaking within three stages, using the suggested system of exercises that consists of corresponding groups (correlating with the stages) and subgroups. The paper also substantiates the criteria for assessing the level of prospective pharmacists in mastering professionally oriented English lexical competence in reading and speaking: the accuracy of understanding, the correctness of guessing a lexical unit's meaning, the adequacy of lexical unit's usage, and lexical concentration. In addition, the paper describes the results of the experiment and validates the data obtained with the help of the multifunctional statistic criterion ∏* - of Fishers angular transformation.

A single-center experience in the use of hybrid techniques for thoracic aortic pathology.

The hybrid method of treating thoracic aortic pathology is devoid of the disadvantages of traditional open surgery and, at the same time, has a broader range of applications than the endovascular method. From 2014 to 2019, we researched 122 patients with thoracic aortic pathology treated with the hybrid method (open surgery with thoracic endovascular aortic repair (TEVAR) at the National M. Amosov Institute of Cardiovascular Surgery National Academy of Medical Science of Ukraine. In the general group, 34 patients had a descending aortic aneurysm without dissection or rupture; 71 patients had an aortic dissection (10 - acute, 9 - subacute, 52 - chronic), penetrating aortic ulcer (PAU) - 7, thoracoabdominal aneurysm (Crawford I-II) - 4, isolated aortic arch aneurysm - 2, residual enlargement aorta after previous ascending aortic grafting causing type A acute aortic dissection (TAAD) - 3, primary aortic thrombosis - 1. Patients admitted as elective surgery candidates had switched aortic arch vessels (debranching) in the first stage and TEVAR in the second stage. For emergencies (aortic rupture with uncontrolled bleeding, malperfusion syndrome), TEVAR operation was performed first. Long-term results of treatment after three and six months are satisfactory. The hybrid technique of aortic arch treatment using modern minimally invasive technologies can eliminate the pathology in the most dangerous segment of the main artery of the body, providing a reasonable level of hospital mortality - 4.2%, and a small number of neurological complications.

The concept of the comorbidity model in predicting laparoscopic cholecystectomy results in patients with acute cholecystitis.

In recent years, there has been an unceasing increase in the number of patients with acute cholecystitis, including those with a complicated course of the disease against the background of concomitant pathology. The aim of the study was to establish the level of comorbidity and its influence on the level of postoperative complications in patients with acute cholecystitis who underwent laparoscopic cholecystectomy. We included 457 patients with acute cholecystitis with accompanying pathology, averaging 64.5±9.74 years. Operative intervention was carried out laparoscopically. Patients who scored 4-3 points were considered favorable, and those who scored 0-2 were considered unfavorable. The assessment of comorbidity was carried out using a special index - the Charlson comorbidity index. The majority of patients had a comorbidity index at 2 points (28.0% of all examined patients), indicating the presence of concomitant pathology in the vast majority of patients. We found that the Charleston comorbidity index increased with age, which indicates a higher frequency of concomitant diseases in older patients. A reliable correlation of medium strength was established (R=0.68; p<0.05) between the age and comorbidity indexes. When predicting the mortality of an experimental cohort of patients with acute cholecystitis who underwent laparoscopic cholecystectomy, it can be predicted that the level of the Charlson comorbidity index correlates with the age of patients while the level of postoperative complications increases.

Isolation of megakaryocytes using magnetic cell separation and adverse effects induced by diclofenac toxicity in an experiment.

This study investigates the response of bone marrow (particularly megakaryocytes) in mice under the influence of diclofenac sodium for 10 days using intraperitoneal injection at various doses. A fundamentally new immunomagnetic separation method was applied during the experiment, which helped obtain pure lines of bone marrow cells, particularly megakaryocytes (MC), without admixtures of other cells or their particles. The resulting cells completely retain their structure and can be used in further research. The study determined that different doses of diclofenac sodium have different effects on different groups of diabetes mellitus cells CD34-megakaryocytes. The use of 1.0 mg/ml sharply negatively affects the state of early populations of megakaryocytes (decrease by 80%, p=0.05), a dose of 0.025 mg/ml had the least effect on this population of cells (22.8%, p=0.05). The greatest number of average forms of diabetes mellitus 34 was observed when using a dose of 0.95 mg/ml (22.8%, p=0.05), with a gradual decrease in the dose, the indicator of this group of cells decreased. A dose of 0.03 mg/ml did not affect the quantitative state of megakaryocytes, and a dose of 0.025 mg/ml caused a slight decrease (16.6%, p=0.05). Indicators of mature cells of megakaryocytes CD 34- decreased in all studied groups, however, their maximum value reached a maximum decrease by 0.25 mg/ml (55.2%, p=0.05), the dose of diclofenac sodium 0.03 mg/ml, lower (18.4%, p=0.05). Diclofenac sodium in different doses has different effects on the degree of differentiation of CD 34-. Its introduction positively affects the state of intermediate forms of megakaryocytes, except for minimal doses, while the effect on early and mature forms in all cases turned out to be negative.

Phosphorus metabolism disorders in erythrocytes and lymphocytes among patients with inflammatory breast cancer, infiltrative stomach and colorectal cancer.

Energy and plastic potential dysfunction of erythrocytes and lymphocytes among people with inflammatory breast cancer, infiltrative stomach cancer, and infiltrative colon cancer is characterized by a more aggressive clinical course and poor prognosis. We explored the features of energy metabolism and phosphorus metabolism disorders in the erythrocytes and lymphocytes of patients with inflammatory breast cancer, infiltrative stomach cancer, and infiltrative colon cancer as a predicting factor in the course of the disease. 49 people were examined; the 1st group had infiltrative stomach cancer (n=17); the 2nd group had infiltrative colon cancer (n=11); the 3rd group had inflammatory breast cancer (n=21). Glycerol-3-phosphate dehydrogenase activity was 1.8 times reduced (p≤0.005), and the activity of glyceraldehyde-3-phosphate dehydrogenase in erythrocytes of patients with cancer at the main localization increased 2.5 times, compared with normal. Inflammatory breast cancer patients had a statistically significant decrease (p<0.005) in erythrocytes adenosine triphosphate content by an average of 56.5% compared with the normal ratio, and in cases of patients with gastric and colorectal cancer, a decrease of 67%. Excessive use of phosphorus for energy metabolism and adenosine triphosphate production destroys the balance of energetic and plastic potentials of erythrocytes and lymphocytes in inflammatory breast cancer, infiltrative stomach, and infiltrative colorectal cancers patients.

HER2/positive and HER2/low in inflammatory breast cancer recurrence.

This study aimed to investigate the impact of HER2-low on the risk of recurrence in individuals with inflammatory breast cancer (IBC). 60 females with HER2-low and HER2-positive IBC underwent surgery between July 2020 and July 2022. Patients were divided into three groups of 20 patients: (1) HRplus/HER2-, (2) HRplus/HERplus, and (3) HR-/HER2plus. All patients underwent chemotherapy in adjuvant mode, following this scheme: TCH=docetaxel and carboplatin plus Herceptin (HER2 target - 4 mg/kg as the loading dose and 6 mg/kg as subsequent doses throughout every 21 days, entire 52 weeks of Herceptin therapy). HRplus/HERplus group had an OS of 76.9% compared with 77.0% in the group with the HRplus/HER2plus subtype and 74.4% in the HR-/HER2plus group. Moreover, recurrence-free survival was 19.1% for the HRplus/HER2- group, 21.3% for the HRplus/HERplus group, and 11.7% for the HR-/HER2plus group. In our study, patients with HER2-low IBC could acquire a perfect response with preliminary systemic therapy, without disease progression or with stable disease on target alone. Further examination is important to decide on the most effective treatment regimens, in addition to mixing chemotherapy with HER2-low-focused on agents.

Management of antibacterial therapy of infectious and inflammatory diseases of the urinary tract in children and regional peculiarities during the COVID-19 pandemic.

Urinary tract infections (UTIs) remain an urgent issue in clinical pediatrics. Empirical selection of antibacterial therapy becomes more complicated, and antibacterial drug indication is not always clinically substantiated. This study aimed to compare the antibacterial susceptibility pattern of the main group of urinary tract infectious agents from 2009-2016 with intermediate results from 2020-2021, during the COVID-19 pandemic, among children in the Chernivtsi region. Urine samples were collected from 3089 children (0-17 years old) treated at the health care institutions in the Chernivtsi region (2009-2016). The clinical-laboratory examination of 177 children (0-17 years old) was carried out from 2020 to 2021. The children received specialized medical care at the Department of Nephrology. Preliminary data of regional monitoring (2020-2021) are not considerably different from the previous regional susceptibility of antibiotics: to penicillin (p<0.01), ІІ-ІІІ generation cephalosporin (p<0.01); an increased resistance to levofloxacin (χ2=4,338; p<0.01), tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01) and imipenem - χ2=5,594; p<0.01). The data obtained did not explain an increased resistance to fluoroquinolones completely (ofloxacin, pefloxacin, ciprofloxacin), except for levofloxacin (χ2=4,338; p<0.01). A reliable difference of susceptibility of tetracycline group was registered (tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01). Furthermore, there was a regional increase in some UTI-pathogen strains resistant to carbapenems (imipenem - χ2=5,594; p<0.01). The use of antibiotics from the group of penicillins and II-III generation cephalosporins as the starting antibacterial therapy for STIs during the COVID-19 pandemic should be justified. A regional increase (2020-2021) of some uropathogenic strains resistant to carbapenems administered to treat severe bacterial infections requires their exclusively designated purpose in everyday pediatric practical work.

The use of hydrolyzed formulas as a method of correction of feeding and clinical rehabilitation of infants with atopy signs.

Our study showed that in formula-fed babies, the use of mixture X (containing 2'-FL (2'-fucosyllactose) - a type of milk oligosaccharide, as well as carefully studied Bifidobacterium lactis, DHA, ARA, and nucleotides) as the main product for feeding could ensure children's body with all the necessary nutrients. Furthermore, it can minimize the progression of clinical signs of atopic dermatitis and reduce the use of drugs. In addition, there was an improvement in height and weight parameters, proportional development of the child (p<0.05), an increase in the number of erythrocytes (erythrocytes), hemoglobin (Hb), mean cell volume (MCV) (p<0.05), a decrease in the number of leukocytes (WBC) (p<0.05), and leveling of skin signs of atopic dermatitis (AD) (according to SCORAD a decrease from 32.8±5.5 to 16.1±2.2, p<0.05). Based on these results, it is possible to recommend using mixture (X) with a preventive and rational purpose as a product of artificial feeding of children with a hereditary predisposition to allergies.

The diverse metabolic heterogeneity of stem cells in a BRCA+/-breast cancer population.

Breast cancers are very heterogeneous tissues constituted by epithelial cancer cells and an abnormal tumor microenvironment - cancer-associated fibroblasts (CAFs), activated adipocytes, mesenchymal stem cells (MSCs), and others. The aim of the study is to cancer cells and their microenvironment, which behave like a complex and heterogeneous metabolic ecosystem, where cancer cells can reprogram their metabolism as a result of interaction with the components of the microenvironment. The study was based on cancer stem cells (CSC) that were isolated from breast tumors by magnetic separation (AutoMACS). We used spectrophotometric methods for the measurement of aldehyde dehydrogenase (ALDH) enzymatic activity. For these experiments, we used breast cancer and normal stem cell lines. Analyses showed that the proportion of BRCA+ CSC cells was in accordance with the relatively low percentages of CSCs in BRCA+ tumors. ALHD was significantly higher in the CSCs-high BRCA+ breast cancer and CSCs-low BRCA- breast cancer cells, compared with the CSCs-low BRCA+ breast cancer. Breast cancer from BRCA mutation carriers harbor more "high-energy" cell sub-populations than "low-energy" and have their more aggressive phenotype. Key oncogenic pathways known to be dysregulated in breast cancer also regulate stem-cell behavior.

Indicators of antioxidant protection of blood in necrotizing ulcerative gingivitis in experimental animals.

This article highlights the results of a study of blood parameters in animals with simulated necrotizing ulcerative gingivitis and compares them, under the same conditions, with animals that received local treatment with a developed complex of antioxidant drugs. Following the work tasks, the nature of changes in the state of the antioxidant - prooxidant system and their influence on quantitative and functional indicators of markers of inflammatory intensity was analyzed and investigated during the pathological process in the background and without treatment with a developed complex. This work shows the changes of malonic dialdehyde concentration as an indicator of lipid peroxidation intensity in experimental animals, the level of catalase activity in the blood of animals, and antioxidant-prooxidant balance in the dynamics of necrotizing ulcerative gingivitis.

State of hormonal balance in adolescent girls with menstrual function disorders associated with obesity.

Investigation of the mechanisms promoting the development of menstrual function disorders associated with obesity in adolescent girls is one of the most important issues of modern medicine. This study included 110 patients. 79 patients aged 12-18 with menstrual disorders associated with obesity were divided into two groups: group 1: 46 patients with apparent signs of hyperandrogenism, group 2: 33 patients without clinical manifestations of hyperandrogenism. The control group included 31 girls of the same age with a regular menstrual cycle. The complex of hormone examination of adolescent girls included determination of serum content: gonadotropic hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH), prolactin (PRL), estradiol (E2), testosterone (T), progesterone (PR), dehydroepiandrosterone sulfate; insulin (In) - radioisotope method on a gamma counter "Narcotest" (reagents "IMMUNOTECH", Czech Republic). We identified hyperleptinemia and leptin resistance in patients with menstrual function impairment associated with obesity. In group I, the adiponectin level exceeded the values of the control group (p<0.05). The results revealed a decrease in A/L in group I - 5.4 times compared with patients in group II (p<0.05) and 4.3 times - compared with the control group (p<0.05). The results revealed a decrease in A/L among girls in the group I with MFI associated with obesity - 4.3 times - compared with girls in the control group (p<0,05).

Influence of anticholinergic drugs on the development of an experimental periodontitis model.

The endogenous microbiome of the oral cavity plays an essential role in the development of periodontal disease. It also has a significant pathogenic effect on the inner-vation of the oral cavity organs. The experimental determination of the effectiveness of various drugs is required for the effective treatment of periodontal disease, and this involves the creation of a model of experimental periodontitis. The objective of this series of studies was to determine the possibility of reproduction of the experimental model of periodontitis and the study of the effects of anticholinergic drugs on the development of an experimental periodontitis model. The reproduction of the experimental model of periodontitis was performed by injecting the gums of rats with solutions of pathogenic factors: lipopolysaccharide, hyaluronidase and trypsin. We aimed to study the effect of anticholinergic drugs (pilocarpine and atropine) on the development of an experimental model of periodontitis after the injection of a hyaluronidase solution (2 mg/ml) into the rats' gums. The study was performed on white Wistar rats. Elastase activity, malonic dialdehyde content, urease activity (bacterial contamination index), lysozyme activity (an indicator of nonspecific immunity), and catalase activity (an antioxidant enzyme) were determined in the homogenate of the studied tissues. The results of a comparative study of the effect of three pathogenic factors (lipopolysaccharide, hyaluronidase, and trypsin) on the activity of elastase in different tissues of experimental animals (gums, tooth pulp, serum, and gastric mucosa) showed that hyaluronidase has the greatest proinflammatory effect. The action of pilocarpine and atropine was determined with an underline experimental periodontitis model. It was shown that both anticholinergic drugs stimulate the inflammatory process in the periodontium and that anticholinergic drugs enhance the proinflammatory effect of hyaluronidase.