Suppression of proliferation, tumorigenicity and metastasis of lung cancer cells after their transduction by interferon-beta gene in baculovirus vector.

BACKGROUND: Gene therapy represents an interesting alternative treatment for cancers. Interferon-beta is well known as a multifunctional cytokine that provides antiviral, antiproliferative, antiangiogenic and immunomodulating effects. For this reason introduction of this cytokine gene in baculovirus vector is seen as a rather promising tool for anticancer therapy. AIM: Investigation of biological behavior in vitro and in vivo of lung cancer cells modified by interferon-beta gene which was introduced into the cells in vitro with baculovirus vector. MATERIALS AND METHODS: Studies were performed on mouse Lewis lung carcinoma cells as the tumor model (LL cell line). Transductions of cells by recombinant baculoviruses, in vitro and in vivo analysis of tumor cell biology and immunocytochemical method have been used. RESULTS: The study of various in vitro biological parameters of LL cancer cells transduced by recombinant baculovirus with interferon gene demonstrated that the transduction of cells is accompanied by significant inhibition of their proliferation and ability to form colonies in semisolid agar. Also, transduction of LL cells with interferon gene inhibited their tumorigenicity, i.e. the ability to cause formation of tumors and metastases in lungs of mice in vivo. Anti-tumor activity of recombinant interferon is realized via high level of its local production in tumors, induced by LL carcinoma cells, transduced with recombinant interferon-beta gene. Recombinant baculovirus without interferon gene did not influence significantly on tumorigenicity and metastatic ability of lung cancer cells. CONCLUSIONS: Introduction of interferon-beta gene in Lewis lung carcinoma cells in vitro in recombinant baculovirus leads to inhibition of their proliferation potential and malignant behavior in vitro, tumorigenicity and metastatic activity in vivo.

Prehabilitation in Cardiovascular Surgery: The Effect of Neuromuscular Electrical Stimulation (Randomized Clinical Trial).

OBJECTIVE: We aimed to determine the effects of prehabilitation with neuromuscular electrical stimulation (NMES) on muscle status and exercise capacity in patients before cardiac surgery. METHODS: Preoperative elective cardiac surgery patients were randomly assigned to the NMES group or control group. Intervention in the NMES group was 7-10 sessions, whereas the control group carried out breathing exercises and an educational program. The outcome measures included a six-minute walk test (6MWT) and a muscle status assessment (knee extensor strength (KES), knee flexor strength (KFS), and handgrip strength (HS)) after the course of prehabilitation. RESULTS: A total of 122 patients (NMES, n = 62; control, n = 60) completed the study. During the NMES course, no complications occurred. After the course prehabilitation KES, KFS, and 6MWT distance were significantly increased (all p < 0.001) in the NMES group compared to the control. There was no significant difference in HS before surgery. CONCLUSIONS: A short-term NMES course before cardiac surgery is feasible, safe, and effective to improve preoperative functional capacity (six-minute walk distance) and the strength of stimulated muscles.

Association of Alternative Markers of Carbohydrate Metabolism (Fructosamine and 1,5-Anhydroglucitol) with Perioperative Characteristics and In-Hospital Complications of Coronary Artery Bypass Grafting in Patients with Type 2 Diabetes Mellitus, Prediabetes, and Normoglycemia.

Patients with type 2 diabetes make up 25 to 40% of those referred for coronary bypass surgery, and the impact of diabetes on the results of the operation is studied in various aspects. To assess the state of carbohydrate metabolism before any surgical interventions, including CABG, daily glycemic control, and the determination of glycated hemoglobin (HbA1c) is recommended. Glycated hemoglobin reflects the glucose concentration for the 3 months prior to the measurement, but alternative markers that reflect glycemic fluctuations over a shorter period of time may be useful in preoperative preparation. The aim of this study was to study the relationship between the concentration of alternative markers of carbohydrate metabolism (fructosamine and 1,5-anhydroglucitol) with patients' clinical characteristics and the rate of hospital complications after coronary artery bypass grafting (CABG). METHOD: In the cohort of 383 patients, besides the routine examination, additional markers of carbohydrate metabolism were determined before and on days 7-8 after CABG: glycated hemoglobin (HbA1c), fructosamine, and 1,5-anhydroglucitol. We evaluated the dynamics of these parameters in groups of patients with diabetes mellitus, prediabetes, and normoglycemia, as well as the association of these parameters with clinical parameters. Additionally, we assessed the incidence of postoperative complications and factors associated with their development. RESULTS: In all groups of patients (diabetes mellitus, prediabetes, normoglycemia), there was a significant decrease in the level of fructosamine on the 7th day after CABG compared with baseline (p1st-2nd point 0.030, 0.001, and 0.038 in groups 1, 2, and 3, respectively), whereas the level of 1,5-anhydroglucitol did not change significantly. The preoperative level of fructosamine was associated with the risk of surgery according to the EuroSCORE II scale (p = 0.002), as were the number of bypasses (p = 0.012), body mass index and overweightness (p < 0.001 in both cases), triglyceride (p < 0.001) and fibrinogen levels (p = 0.002), preoperative and postoperative glucose and HbA1c levels (p < 0.001 in all cases), left atrium size (p = 0.028), multiplicity of cardioplegia, cardiopulmonary bypass duration and aortic clamp time (p < 0.001 in all cases). The preoperative level of 1,5-anhydroglucitol showed an inverse correlation with fasting glucose and fructosamine levels before surgery (p < 0.001 in all cases), intima media thickness (p = 0.016), and a direct correlation with LV end-diastolic volume (p = 0.020). The combined endpoint (presence of significant perioperative complications + extended hospital stay after surgery >10 days) was identified in 291 patients. In binary logistic regression analysis patient age (p = 0.005) and fructosamine level (p = 0.022) were independently associated with the development of this composite endpoint (presence of significant perioperative complications + extended hospital stay after surgery >10 days). CONCLUSIONS: This study demonstrated that in patients after CABG there was the significant decrease in the level of fructosamine compared with baseline, whereas the level of 1,5-anhydroglucitol did not change. Preoperative fructosamine levels were one of the independent predictors of the combined endpoint. The prognostic value of preoperative assessment of alternative markers of carbohydrate metabolism in cardiac surgery deserves further study.

The Role of Insulin Resistance in the Development of Complications after Coronary Artery Bypass Grafting in Patients with Coronary Artery Disease.

The aim of the study was to investigate the effect of carbohydrate metabolism disorders and insulin resistance indices on the immediate results of coronary artery bypass grafting (CABG). METHOD: Patients with coronary artery disease who underwent CABG (n = 383) were examined to determine glycemic status, free fatty acid and fasting insulin levels, and insulin resistance indices (Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), McAuley index, Quantitative Insulin Sensitivity Check Index (QUICKI), Revised-QUICKI). Patients were assessed for the development of perioperative complications and their length of stay in the hospital. Two groups were formed: group 1, patients with a combined endpoint (CEP, any complication and/or duration of hospital stay >10 days), n = 291; and group 2 (n = 92) without a CEP. Perioperative characteristics were analyzed, and predictors of hospital complications and prolonged hospital stay were evaluated. RESULTS: Patients in the CEP group were older, and there were more women among them (p = 0.003). Additionally, in this group, there were more patients with diabetes mellitus (37.5% vs 17.4%, p < 0.001), obesity (p < 0.001), and a higher percentage of combined operations (p = 0.007). In the group with a CEP, the levels of glucose (p = 0.031), glycated hemoglobin (p = 0.009), and free fatty acids (p = 0.007) and the Revised-QUICKI (p = 0.020) were higher than in the group without complications. In a regression analysis, the independent predictors of complications were combined operations (p = 0.016) and the predictors of a long hospital stay (>14 days) were female gender, the left atrium size, and diabetes mellitus (p < 0.001). The predictors of a composite endpoint included female gender, age, the left atrium size, and free fatty acid levels (p < 0.001). CONCLUSIONS: In the group with in-hospital complications after CABG, not only was the presence of diabetes mellitus more often detected, but there were also higher levels of free fatty acids and a higher Revised-QUICKI. Therefore, additional assessments of insulin resistance and free fatty acid levels are advisable in patients before CABG.

Factors Determining the Functional State of Cardiac Surgery Patients with Complicated Postoperative Period.

The purpose of this work was to study the factors determining the functional state of cardiac surgery patients with a complicated postoperative period upon discharge from the hospital. This observational study included 60 patients who underwent cardiac surgery with a complicated postoperative course and with a prolonged intensive care unit stay of more than 72 h. We assessed handgrip and lower-extremity muscle strength and the six-minute walk test (6MWT) distance 3 days after the surgery and at discharge from the hospital. Some patients (53%) additionally underwent a course of neuromuscular electrostimulation (NMES). Two groups of patients were formed: first (6MWT distance at discharge of more than 300 m) and second groups (6MWT distance of 300 m or less). The patients of the second group had less lower-extremity muscle strength and handgrip strength on the third postoperative day, a longer aortic clamping time and a longer stay in the intensive care unit. Independent predictors of decreased exercise tolerance at discharge were body mass index, foot extensor strength and baseline 6MWT distance in the general group, duration of cardiopulmonary bypass in the NMES group and in the general group, and age in the NMES group. Thus, the muscle status on the third postoperative day was one of the independent factors associated with the 6MWT distance at discharge in the general group, but not in patients who received NMES. It is advisable to use these results in patients with complications after cardiac surgery with the use of NMES rehabilitation.

Cardio-Ankle Vascular Index in the Persons with Pre-Diabetes and Diabetes Mellitus in the Population Sample of the Russian Federation.

The aim of this study was to evaluate Cardio-Ankle Vascular Index (CAVI) and increased arterial stiffness predictors in patients with carbohydrate metabolism disorders (CMD) in the population sample of Russian Federation. METHODS: 1617 patients (age 25-64 years) were enrolled in an observational cross-sectional study Epidemiology of Cardiovascular Diseases and Their Risk Factors in the Regions of the Russian Federation (ESSE-RF). The standard ESSE-RF protocol has been extended to measure the cardio-ankle vascular index (CAVI), a marker of arterial stiffness. Patients were divided into three groups: patients with type 2 diabetes mellitus (n = 272), patients with prediabetes (n = 44), and persons without CMD (n = 1301). RESULTS: Median CAVI was higher in diabetes and prediabetes groups compared with group without CMD (p = 0.009 and p < 0.001, respectively). Elevated CAVI (≥9.0) was detected in 16.8% of diabetes patients, in 15.9% of those with prediabetes, and in 9.0% of those without CMD (p < 0.001). The factors affecting on CAVI did not differ in CVD groups. In logistic regression the visceral obesity, increasing systolic blood pressure (SBP) and decreasing glomerular filtration rate (GFR) were associated with a pathological CAVI in CMD patients, and age, diastolic blood pressure (DBP), and cholesterol in persons without CMD. CONCLUSIONS: the CAVI index values in the prediabetes and diabetes patients were higher than in normoglycemic persons in a population sample of the Russian Federation. Since the identified disorders of arterial stiffness in prediabetes are similar to those in diabetes, their identification is important to prevent further cardiovascular complications.

Screening for Glucose Metabolism Disorders, Assessment the Disse Insulin Resistance Index and Hospital Prognosis of Coronary Artery Bypass Surgery.

OBJECTIVE: To study insulin resistance markers and their relationship with preoperative status and hospital complications of coronary artery bypass grafting (CABG) in patients with type 2 diabetes, prediabetes and normoglycemia. METHODS: We included 383 consecutive patients who underwent CABG. Patients were divided into two groups-with carbohydrate metabolism disorders (CMD, n = 192) and without CMD (n = 191). Free fatty acids and fasting insulin in plasma were determined, and the Disse, QUICKI and revised QUICKI indices were calculated in all patients. Perioperative characteristics and postoperative complications were analyzed in these groups, and their relations with markers of insulin resistance. RESULTS: Screening before CABG increased the number of patients with CMD from 25.3% to 50.1%. Incidence of postoperative stroke (p = 0.044), and hospital stay after CABG > 30 days (p = 0.014) was greater in CMD patients. Logistic regression analysis revealed that an increase in left atrial size, age, aortic clamping time, and decrease in Disse index were independently associated with hospital stay >10 days and/or perioperative complications. CONCLUSIONS: Screening for CMD before CABG increased the patient number with prediabetes and type 2 diabetes. In the CMD group, there were more frequent hospital complications. The Disse index was an independent predictor of long hospital stay and/or poor outcomes.

Iron metabolism disturbances in the MCF-7 human breast cancer cells with acquired resistance to doxorubicin and cisplatin.

The development of resistance of cancer cells to therapeutic agents is the major obstacle in the successful treatment of breast cancer and the main cause of breast cancer recurrence. The results of several studies have demonstrated an important role of altered cellular iron metabolism in the progression of breast cancer and suggested that iron metabolism may be involved in the acquisition of a cancer cell drug-resistant phenotype. In the present study, we show that human MCF-7 breast cancer cells with an acquired resistance to the chemotherapeutic drugs doxorubicin (MCF-7/DOX) and cisplatin (MCF-7/CDDP) exhibited substantial alterations in the intracellular iron content and levels of iron-regulatory proteins involved in the cellular uptake, storage and export of iron, especially in profoundly increased levels of ferritin light chain (FTL) protein. The increased levels of FTL in breast cancer indicate that FTL may be used as a diagnostic and prognostic marker for breast cancer. Additionally, we demonstrate that targeted downregulation of FTL protein by the microRNA miR-133a increases sensitivity of MCF-7/DOX and MCF-7/CDDP cells to doxorubicin and cisplatin. These results suggest that correction of iron metabolism abnormalities may substantially improve the efficiency of breast cancer treatment.