From the Catastrophic Objective Irreproducibility of Cancer Research and Unavoidable Failures of Molecular Targeted Therapies to the Sparkling Hope of Supramolecular Targeted Strategies.

The unprecedented non-reproducibility of the results published in the field of cancer research has recently come under the spotlight. In this short review, we try to highlight some general principles in the organization and evolution of cancerous tumors, which objectively lead to their enormous variability and, consequently, the irreproducibility of the results of their investigation. This heterogeneity is also extremely unfavorable for the effective use of molecularly targeted medicine. Against the seemingly comprehensive background of this heterogeneity, we single out two supramolecular characteristics common to all tumors: the clustered nature of tumor interactions with their microenvironment and the formation of biomolecular condensates with tumor-specific distinctive features. We suggest that these features can form the basis of strategies for tumor-specific supramolecular targeted therapies.

Efficient Selection of Enhancers and Promoters from MIA PaCa-2 Pancreatic Cancer Cells by ChIP-lentiMPRA.

A library of active genome regulatory elements (putative promoters and enhancers) from MIA PaCa-2 pancreatic adenocarcinoma cells was constructed using a specially designed lentiviral vector and a massive parallel reporter assay (ChIP-lentiMPRA). Chromatin immunoprecipitation of the cell genomic DNA by H3K27ac antibodies was used for primary enrichment of the library for regulatory elements. Totally, 11,264 unique genome regions, many of which are capable of enhancing the expression of the CopGFP reporter gene from the minimal CMV promoter, were identified. The regions tend to be located near promoters. Based on the proximity assay, we found an enrichment of highly expressed genes among those associated with three or more mapped distal regions (2 kb distant from the 5'-ends of genes). It was shown significant enrichment of genes related to carcinogenesis or Mia PaCa-2 cell identity genes in this group. In contrast, genes associated with 1-2 distal regions or only with proximal regions (within 2 kbp of the 5'-ends of genes) are more often related to housekeeping functions. Thus, ChIP-lentiMPRA is a useful strategy for creating libraries of regulatory elements for the study of tumor-specific gene transcription.

Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.

BACKGROUND: In patients who underwent cardiac surgery, first-time postoperative atrial fibrillation (POAF) is associated with increased incidence of hospital-acquired complications and mortality. Systemic inflammation is one of confirmed triggers of its development. The anti-inflammatory properties of colchicine can be effective for the POAF prevention. However, the results of several studies were questionable and required further investigation. Hence, we aimed to evaluate the effectiveness of low-dose short-term colchicine administration for POAF prevention in patients after the open-heart surgery. This double-blind randomized placebo-controlled trial included 267 patients, but 27 of them dropped out in the course of the study. Study subjects received the test drug on the day before the surgery and on postoperative days 2, 3, 4 and 5. The rhythm control was conducted immediately after the operation and until the discharge from the hospital. The final analysis included 240 study subjects: 113 in the colchicine group and 127 in the placebo group. POAF was observed in 21 (18.6%) patients of the colchicine group vs. 39 (30.7%) control patients (OR 0.515; 95% Cl 0.281-0.943; p = 0.029). We observed no statistically significant differences between the patient groups in the secondary endpoints of the study (hospital mortality, respiratory failure, stroke, bleeding, etc.). For other parameters characterizing the severity of inflammation (pericardial effusion, pleural effusion, WBC count, neutrophil count), there were statistically significant differences between the groups in the early postoperative period (days 3 and 5). Also, statistically significant differences between the groups in the frequency of adverse events were revealed: the incidence of diarrhea in the colchicine group was 25.7% vs. 11.8% in the placebo group (OR 2.578; 95% Cl 1.300-5.111; p = 0.005); for abdominal pain, incidence values were 7% vs. 1.6%, correspondingly (OR 4.762; 95% Cl 1.010-22.91; p = 0.028). Thus, there were statistically significant differences between groups in the primary endpoint, thereby confirming the effectiveness of short-term colchicine use for the POAF prevention after coronary artery bypass grafting and/or aortic valve replacement. Also, we detected statistically significant differences between groups in the frequency of side effects to colchicine: diarrhea and abdominal pain were more common in the colchicine group. This clinical trial is registered with ClinicalTrials database under a unique identifier: NCT04224545.

Survival and freedom from reoperation after the Ross procedure in a Russian adult population: A single-center experience.

Objectives: To evaluate our 12-year experience with the Ross procedure in adults. Methods: A retrospective analysis of 215 cases of the Ross procedure was performed. The mean age of the patients was 36 ± 11.1 years, and the male to female ratio was 75% to 25%, respectively. The pulmonary autograft was placed into the aortic position using the full-root replacement technique and its modified versions. The right ventricular outflow tract was reconstructed using a pulmonary homograft in all cases. Results: The 30-day mortality after the operation was 0.9% (2 patients). The median duration of follow-up was 6.1 years (interquartile range, 6.5 years) and was complete in 86% of cases. The survival at 12 years was 94.7% and was comparable with the survival rate of the general population matched for age and sex. At the end of the follow-up, freedom from reoperation due to pulmonary autograft and homograft dysfunction was 89.1% and 99%, respectively. Conclusions: In our series, the Ross procedure resulted in low early mortality and excellent survival in adults. The long-term survival was not statistically different from the survival of the general population. The pulmonary homograft offered an excellent durability and freedom from reoperation.

Data Incompleteness May form a Hard-to-Overcome Barrier to Decoding Life's Mechanism.

In this brief review, we attempt to demonstrate that the incompleteness of data, as well as the intrinsic heterogeneity of biological systems, may form very strong and possibly insurmountable barriers for researchers trying to decipher the mechanisms of the functioning of live systems. We illustrate this challenge using the two most studied organisms: E. coli, with 34.6% genes lacking experimental evidence of function, and C. elegans, with identified proteins for approximately 50% of its genes. Another striking example is an artificial unicellular entity named JCVI-syn3.0, with a minimal set of genes. A total of 31.5% of the genes of JCVI-syn3.0 cannot be ascribed a specific biological function. The human interactome mapping project identified only 5-10% of all protein interactions in humans. In addition, most of the available data are static snapshots, and it is barely possible to generate realistic models of the dynamic processes within cells. Moreover, the existing interactomes reflect the de facto interaction but not its functional result, which is an unpredictable emerging property. Perhaps the completeness of molecular data on any living organism is beyond our reach and represents an unsolvable problem in biology.

SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner.

SOX9 is upregulated in the majority of pancreatic ductal adenocarcinoma cases. It is hypothesized that the increased expression of SOX9 is necessary for the formation and maintenance of tumor phenotypes in pancreatic cancer cells. In our research, we studied six pancreatic cancer cell lines, which displayed varying levels of differentiation and a range of oncogenic mutations. We chose the method of downregulation of SOX9 expression via siRNA transfection as the main method for investigating the functional role of the SOX9 factor in pancreatic cancer cells. We discovered that the downregulation of SOX9 expression in the cell lines leads to cell-line-specific changes in the expression levels of epithelial and mesenchymal protein markers. Additionally, the downregulation of SOX9 expression had a specific effect on the expression of pancreatic developmental master genes. SOX9 downregulation had the greatest effect on the expression levels of the protein regulators of cell proliferation. In three of the four cell lines studied, the transfection of siSOX9 led to a significant decrease in proliferative activity and to the activation of proapoptotic caspases in transfected cells. The acquired results demonstrate that the SOX9 protein exerts its multiple functions as a pleiotropic regulator of differentiation and a potential promoter of tumor growth in a cell-specific manner in pancreatic cancer cells.

Influence of constant lightning on liver health: an experimental study.

Light pollution has become a serious problem in many urbanized areas of the world. The impact of prolonged exposure to light and consequent disruption of natural circadian rhythms has significant health implications. The current study was undertaken to evaluate the effect of prolonged exposure to light, simulating urban light pollution, on liver health. In order to evaluate the effect of prolonged exposure to light, we examined the morphofunctional state, immunohistochemical and micromorphometric parameters of rat liver in normal conditions and following prolonged lighting exposure. Our results show that nocturnal light disruption triggers a cell death in the liver within 3 weeks (necrosis and apoptosis of hepatocytes) and stimulates a change in normal cellular karyometric parameters. At the same time, intracellular regeneration takes place within the organ, which manifests through hepatocyte hypertrophy. Under the influence of constant illumination, the circadian rhythms (CRs) of the size of hepatocytes and their nuclei are restructured, and the rhythm of the nuclear-cytoplasmic ratio is destroyed. The destruction of the CR of expression of p53 and Ki-67 also occurs against the background of the rearrangement of the daily rhythmicity of Per2 and Bmal1. The revealed changes in the morphofunctional state of the liver under the influence of light pollution indicate that a violation of normal illumination regimes is a potent factor leading to significant structural changes in the liver.

Risk Factors for Deep Sternal Wound Infection after Off-Pump Coronary Artery Bypass Grafting: a Case-Control Study

Abstract Introduction: The objective of this study was to identify risk factors for deep sternal wound infection (DSWI) after off-pump coronary artery bypass (OPCAB) grafting surgery. Methods: A total of 8,442 patients undergoing OPCAB from April 1, 2009 to December 31, 2018 were retrospectively analyzed. A total of 956 were eventually enrolled on this study based on our exclusion criteria. All subjects were divided into two groups: group 1 (n=63) - DSWI; group 2 (n=893) - without DSWI. Patients were excluded if they had one of the following: acute coronary syndrome, conversion to OPCAB grafting surgery, redo procedure, concomitant cardiac surgery procedures. Results: The prevalence of body mass index (BMI) ≥40 kg/m2 (7.9% vs. 1.9%, respectively; P=0.01), lower extremity atherosclerotic artery disease (23.8% vs. 7.2%, respectively; P=0.001) and use of bilateral internal thoracic artery (19.5% vs. 2.5%, respectively; P=0.008) was significantly higher in patients with DSWI. The incidence of morbidities, including reoperation for bleeding (26.4% vs. 2.1%, respectively; P<0.001), stroke (4.8% vs. 0.8%, respectively; P=0.02), acute renal failure (7.9% vs. 0.8%, respectively; P=0.001), delirium (7.9% vs. 1.7%, respectively; P=0.008) and blood transfusion (30.6% vs. 9.8%, respectively; P<0.001) was significantly higher in patients with DSWI. Conclusions: A BMI of >40 kg/m2, lower extremity artery disease, use of bilateral internal thoracic artery (BITA) graft, postoperative stroke, sepsis, reoperation due to postoperative complications and blood product requirement significantly increased the risk of sternal infection after OPCAB.

Risk Factors for Deep Sternal Wound Infection after Off-Pump Coronary Artery Bypass Grafting: a Case-Control Study.

INTRODUCTION: The objective of this study was to identify risk factors for deep sternal wound infection (DSWI) after off-pump coronary artery bypass (OPCAB) grafting surgery. METHODS: A total of 8,442 patients undergoing OPCAB from April 1, 2009 to December 31, 2018 were retrospectively analyzed. A total of 956 were eventually enrolled on this study based on our exclusion criteria. All subjects were divided into two groups: group 1 (n=63) - DSWI; group 2 (n=893) - without DSWI. Patients were excluded if they had one of the following: acute coronary syndrome, conversion to OPCAB grafting surgery, redo procedure, concomitant cardiac surgery procedures. RESULTS: The prevalence of body mass index (BMI) ≥40 kg/m2 (7.9% vs. 1.9%, respectively; P=0.01), lower extremity atherosclerotic artery disease (23.8% vs. 7.2%, respectively; P=0.001) and use of bilateral internal thoracic artery (19.5% vs. 2.5%, respectively; P=0.008) was significantly higher in patients with DSWI. The incidence of morbidities, including reoperation for bleeding (26.4% vs. 2.1%, respectively; P<0.001), stroke (4.8% vs. 0.8%, respectively; P=0.02), acute renal failure (7.9% vs. 0.8%, respectively; P=0.001), delirium (7.9% vs. 1.7%, respectively; P=0.008) and blood transfusion (30.6% vs. 9.8%, respectively; P<0.001) was significantly higher in patients with DSWI. CONCLUSIONS: A BMI of >40 kg/m2, lower extremity artery disease, use of bilateral internal thoracic artery (BITA) graft, postoperative stroke, sepsis, reoperation due to postoperative complications and blood product requirement significantly increased the risk of sternal infection after OPCAB.

Morphofunctional State and Circadian Rhythms of the Liver under the Influence of Chronic Alcohol Intoxication and Constant Lighting.

A study of the influence of chronic alcohol intoxication, constant illumination and their combined effects on the morphofunctional state of the rat liver and the circadian rhythms (CR) of the studied parameters of the organism was carried out. It was found that both alcohol and constant illumination caused significant changes in the structure of the liver, as well as in the circadian rhythmicity of micromorphometric parameters of hepatocytes, ALT, and total and direct bilirubin rhythms; however, the combined effects of ethanol and constant illumination had the most significant effect on the studied parameters of the organism. These two factors caused disturbances in the circadian rhythms of the micromorphometric parameters of hepatocytes, disruption of the circadian rhythms of total protein, albumin, AST, ALT, and direct and total bilirubin, as well as disturbances in the expression and rhythmicity of the studied clock genes against a background of the development of an inflammatory process in the liver.

Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells.

Intercellular interactions involving adhesion factors are key operators in cancer progression. In particular, these factors are responsible for facilitating cell migration and metastasis. Strengthening of adhesion between tumor cells and surrounding cells or extracellular matrix (ECM), may provide a way to inhibit tumor cell migration. Recently, we demonstrated that PDX1 ectopic expression results in the reduction of pancreatic cancer line PANC-1 cell motility in vitro and in vivo, and we now provide experimental data confirming the hypothesis that suppression of migration may be related to the effect of PDX1 on cell adhesion. Cell migration analyses demonstrated decreased motility of pancreatic Colo357 and PANC-1 cell lines expressing PDX1. We observed decreased expression levels of genes associated with promoting cell migration and increased expression of genes negatively affecting cell motility. Expression of the EMT regulator genes was only mildly induced in cells expressing PDX1 during the simulation of the epithelial-mesenchymal transition (EMT) by the addition of TGFß1 to the medium. PDX1-expressing cancer cell lines showed increased cell adhesion to collagen type I, fibronectin, and poly-lysine. We conclude that ectopic expression of PDX1 reduces the migration potential of cancer cells, by increasing the adhesive properties of cells and reducing the sensitivity to TGFß1-induced EMT.

Immediate Outcomes of Aortic Valve Neocuspidization with Glutaraldehyde-treated Autologous Pericardium: a Multicenter Study.

OBJECTIVE: To determine the feasibility of aortic valve neocuspidization (AVNeo) with glutaraldehyde-treated autologous pericardium. METHODS: One hundred and seventy (170) AVNeo (84 males/86 females) were performed from January 2017 through March 2019 in three centers. All the records were prospectively collected and retrospectively reviewed. RESULTS: Most of the patients were older than 60 years and over 95% were operated for aortic stenosis. Preoperatively, pressure gradients were 69.9±21.3 mmHg for patients with aortic stenosis, and the surgical annular diameter was 21.0±2.0 mm for all patients. Effective orifice area (EOA) and indexed EOA (iEOA) averaged 0.7±0.3 cm2 and 0.4±0.2 cm2/m2 for patients with aortic stenosis before surgery, respectively. There was no conversion to prosthetic aortic valve replacement. Eight patients needed reoperation for bleeding, but no patient needed reoperation due to early infective endocarditis. There were five in-hospital deaths due to noncardiac cause. Compared to preoperative echocardiographic measurements, postoperative peak pressure gradient decreased significantly (-58.7±1.7 mmHg; P<0.001) and reached 11.2±5.6 mmHg, and mean pressure gradient also decreased significantly (-36.8±1.1 mmHg; P<0.001) and reached 6.0±3.5 mmHg. Accordingly, EOA and iEOA increased significantly 2.0 cm2 and 1.0 cm2/m2 (both P<0.001) to reach 2.7±0.6 cm2 and 1.4±0.3 cm2/m2 after surgery, respectively, with minimal significant aortic regurgitation (0.6% > mild). CONCLUSION: AVNeo is feasible and reproducible with good clinical results. Hemodynamically, AVNeo produces immediate postoperative low-pressure gradients, large EOA, and minimal regurgitation of the aortic valve. Further studies are necessary to evaluate mid- and long-term evolution.

Immediate outcomes of aortic valve neocuspidization with glutaraldehyde-treated autologous pericardium: a multicenter study

Abstract Objective: To determine the feasibility of aortic valve neocuspidization (AVNeo) with glutaraldehyde-treated autologous pericardium. Methods: One hundred and seventy (170) AVNeo (84 males/86 females) were performed from January 2017 through March 2019 in three centers. All the records were prospectively collected and retrospectively reviewed. Results: Most of the patients were older than 60 years and over 95% were operated for aortic stenosis. Preoperatively, pressure gradients were 69.9±21.3 mmHg for patients with aortic stenosis, and the surgical annular diameter was 21.0±2.0 mm for all patients. Effective orifice area (EOA) and indexed EOA (iEOA) averaged 0.7±0.3 cm2 and 0.4±0.2 cm2/m2 for patients with aortic stenosis before surgery, respectively. There was no conversion to prosthetic aortic valve replacement. Eight patients needed reoperation for bleeding, but no patient needed reoperation due to early infective endocarditis. There were five in-hospital deaths due to noncardiac cause. Compared to preoperative echocardiographic measurements, postoperative peak pressure gradient decreased significantly (-58.7±1.7 mmHg; P<0.001) and reached 11.2±5.6 mmHg, and mean pressure gradient also decreased significantly (-36.8±1.1 mmHg; P<0.001) and reached 6.0±3.5 mmHg. Accordingly, EOA and iEOA increased significantly 2.0 cm2 and 1.0 cm2/m2 (both P<0.001) to reach 2.7±0.6 cm2 and 1.4±0.3 cm2/m2 after surgery, respectively, with minimal significant aortic regurgitation (0.6% > mild). Conclusion: AVNeo is feasible and reproducible with good clinical results. Hemodynamically, AVNeo produces immediate postoperative low-pressure gradients, large EOA, and minimal regurgitation of the aortic valve. Further studies are necessary to evaluate mid- and long-term evolution.

Minithoracotomy vs. Conventional Mitral Valve Surgery for Rheumatic Mitral Valve Stenosis: a Single-Center Analysis of 128 Patients.

OBJECTIVE: To compare the in-hospital outcomes of a right-sided anterolateral minithoracotomy with those of median sternotomy in patients who received a mitral valve replacement (MVR) because of rheumatic mitral valve stenosis (RMS). METHODS: This is a retrospective analysis of 128 patients (34% male) with RMS between 2011 and 2015. The median age was 53 years (45; 56). The mean ejection fraction was 58.4±6.3%. All the subjects were divided into two groups - Group 1 contained 78 patients who underwent MVR via minithoracotomy (MT-MVR), while Group 2 contained 50 patients who underwent MVR via median sternotomy (S-MVR). RESULTS: In the MT-MVR group, a mechanical prosthesis was implanted in 72% of cases, while it was implanted in 90% of cases in the S-MVR group (P=0.01). The duration of myocardial ischemia was similar (MT-MVR, 77±24 min; S-MVR, 70±18 min) (P=0.09). However, the cardiopulmonary bypass time was lower in the S-MVR group than in the MT-MVR group (99±24 min and 119±34 min, respectively) (P≤0.001). There was no difference in the duration of mechanical ventilation, intensive care unit stay, and hospitalization period. Postoperative blood loss was lower in the MT-MVR group (P≤0.001) than in the S-MVR group. There are no statistically significant differences in postoperative complications (superficial wound infection, stroke, delirium, pericardial tamponade, pleural puncture, acute kidney insufficiency, and implantation of pacemaker). The overall in-hospital mortality was 3.9% (P=0.6). CONCLUSION: The minimally invasive approach for RMS is feasible and has an excellent cosmetic effect without increasing the risk of surgical complications.

Are Synapse-Like Structures a Possible Way for Crosstalk of Cancer with Its Microenvironment?

The failure of therapies directed at targets within cancer cells highlight the necessity for a paradigm change in cancer therapy. The attention of researchers has shifted towards the disruption of cancer cell interactions with the tumor microenvironment. A typical example of such a disruption is the immune checkpoint cancer therapy that disrupts interactions between the immune and the cancer cells. The interaction of cancer antigens with T cells occurs in the immunological synapses. This is characterized by several special features, i.e., the proximity of the immune cells and their target cells, strong intercellular adhesion, and secretion of signaling cytokines into the intercellular cleft. Earlier, we hypothesized that the cancer-associated fibroblasts interacting with cancer cells through a synapse-like adhesion might play an important role in cancer tumors. Studies of the interactions between cancer cells and cancer-associated fibroblasts showed that their clusterization on the membrane surface determined their strength and specificity. The hundreds of interacting pairs are involved in the binding that may indicate the formation of synapse-like structures. These interactions may be responsible for successful metastasis of cancer cells, and their identification and disruption may open new therapeutic possibilities.

Ligation of Left Atrial Appendage during Off-Pump Coronary Surgery.

OBJECTIVE: The main purpose of this article is to evaluate an impact of epicardial ligation of the left atrial appendage (LAA) in patients with atrial fibrillation (AF) undergoing off-pump coronary artery bypass grafting (OPCAB) on the development of ischemic stroke and mortality. METHODS: From 2009 to 2013, a total of 125 patients (86.4% men, mean age 64 ± 7 years, 95% confidence interval: 61-65 years) received a combined OPCAB and LAA ligation because of coronary artery disease and AF. All the subjects were divided into two groups: group 1 (n = 57)-LAA ligation during OPCAB, group 2 (n = 68) without LAA ligation during OPCAB. Primary endpoints were postoperative incidence of ischemic stroke and mortality. RESULTS: No difference in the number of ischemic stroke (0 vs. 5.9%) and death (0 vs. 4.4%) in both groups during the hospital period (p > 0.05). Median overall follow-up was 41 (22-61) months: without difference for groups (p > 0.05). During follow-up, there was a difference in the number of ischemic stroke (0 vs. 17.6%, p < 0.001), while there was no difference in mortality in two study groups (5.3 vs. 16.2%, p > 0.05). CONCLUSION: Epicardial ligation of LAA during OPCAB in patients with AF may reduce the risk of ischemic stroke in long-term follow-up and does not affect the mortality.

Minithoracotomy vs. conventional mitral valve surgery for rheumatic mitral valve stenosis: a single-center analysis of 128 patients

Abstract Objective: To compare the in-hospital outcomes of a right-sided anterolateral minithoracotomy with those of median sternotomy in patients who received a mitral valve replacement (MVR) because of rheumatic mitral valve stenosis (RMS). Methods: This is a retrospective analysis of 128 patients (34% male) with RMS between 2011 and 2015. The median age was 53 years (45; 56). The mean ejection fraction was 58.4±6.3%. All the subjects were divided into two groups - Group 1 contained 78 patients who underwent MVR via minithoracotomy (MT-MVR), while Group 2 contained 50 patients who underwent MVR via median sternotomy (S-MVR). Results: In the MT-MVR group, a mechanical prosthesis was implanted in 72% of cases, while it was implanted in 90% of cases in the S-MVR group (P=0.01). The duration of myocardial ischemia was similar (MT-MVR, 77±24 min; S-MVR, 70±18 min) (P=0.09). However, the cardiopulmonary bypass time was lower in the S-MVR group than in the MT-MVR group (99±24 min and 119±34 min, respectively) (P≤0.001). There was no difference in the duration of mechanical ventilation, intensive care unit stay, and hospitalization period. Postoperative blood loss was lower in the MT-MVR group (P≤0.001) than in the S-MVR group. There are no statistically significant differences in postoperative complications (superficial wound infection, stroke, delirium, pericardial tamponade, pleural puncture, acute kidney insufficiency, and implantation of pacemaker). The overall in-hospital mortality was 3.9% (P=0.6) Conclusion: The minimally invasive approach for RMS is feasible and has an excellent cosmetic effect without increasing the risk of surgical complications.

The Russian Conduit - Combining Bentall and Ozaki Procedures for Concomitant Ascending Aorta Replacement and Aortic Valve Neocuspidization.

In aortic valve disease cases, prosthetic valves have been used for valve replacement, however, these prostheses have inherent problems, and their quality in some countries is lower comparing to new-generation models, causing shorter durability. Aortic valve neocuspidization (AVNeo) has emerged as an option, which can be applied to a wide spectrum of these diseases. Despite the promising results, this procedure is not widely spread among cardiac surgeons yet. We developed a surgical technique combining Bentall and Ozaki procedures to treat patients with concomitant ascending aorta replacement and AVNeo and we describe it in this paper.

The Russian conduit - combining bentall and ozaki procedures for concomitant ascending aorta replacement and aortic valve neocuspidization

Abstract In aortic valve disease cases, prosthetic valves have been used for valve replacement, however, these prostheses have inherent problems, and their quality in some countries is lower comparing to new-generation models, causing shorter durability. Aortic valve neocuspidization (AVNeo) has emerged as an option, which can be applied to a wide spectrum of these diseases. Despite the promising results, this procedure is not widely spread among cardiac surgeons yet. We developed a surgical technique combining Bentall and Ozaki procedures to treat patients with concomitant ascending aorta replacement and AVNeo and we describe it in this paper.

PDX1, a key factor in pancreatic embryogenesis, can exhibit antimetastatic activity in pancreatic ductal adenocarcinoma.

Background: In cancer biology, metastasizing is one of the most poorly studied processes. Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastasis, which is the leading cause of death. The PDX1 protein is crucial for the development of cancer, and its low levels are characteristic of the most aggressive PDAC tumors. The PDX1 is a mediator of initiation and progression of PDAC. However, further studies are needed to elucidate the role of PDX1 in the cancer metastasis. Purpose: To confirm the hypothesis that PDX1 in PDAC plays suppressor role of epithelial-mesenchymal transition (EMT), and to study its possible ability to inhibit metastasis. Methods: A PDX1-overexpressing PDAC cell line was obtained by lentiviral transduction of PANC-1 cells. PDX1 overexpression was confirmed by RT-PCR and Western blotting. Effects of PDX1 ectopic expression on cell proliferation and motility were determined in PANC-1 cells using MTS, cell cycle analysis, transwell and wound-healing assay. EMT genes expression was analyzed in PDX1-overexpressing and Control PANC-1. Finally, the migration potential of pancreatic cancer cells expressing PDX1 was evaluated using a zebrafish embryo model. Results: The motility of human PDAC cells PANC-1 considerably decreased at ectopic expression of PDX1. The decreased expression of ZEB1, the key factor of EMT, and almost unchanged expression of the genes that characterize the epithelial state suggest a decrease in the EMT ability. Suppression of PDX1 expression by siRNA knockdown restored the PANC1 motility. Conclusion: The results obtained suggest a possible therapeutic use of PDX1 delivery into PDAC patients with a reduced or absent expression of PDX1 in the most aggressive tumors.