Clinical Impact of Patient-Prosthesis Mismatch After Aortic Valve Replacement With a Mechanical or Biological Prosthesis.

BACKGROUND: Patient-prosthesis mismatch (PPM) may impair functional capacity and survival after aortic valve replacement. This study aimed to investigate the impact of PPM on long-term survival and quality of life after mechanical and biological aortic valve replacement. METHODS: This study included 595 consecutive patients who had undergone isolated aortic valve replacement. Patients were divided into 2 groups according to prosthesis type. The baseline and operative characteristics, survival rates, complications, and quality of life of the groups with and without PPM were compared for up to 6 years. The PPM calculation was performed using the effective orifice area value provided by the manufacturer divided by the patient's body surface area. RESULTS: The moderate to severe PPM rates were 69.8% and 3.7% after biological and mechanical prosthesis implantation, respectively. Mean survival for patients in the biological group who had PPM was statistically significantly shorter (50.2 months [95% CI, 45.2-55.3]) than for patients in the biological group without PPM (60.1 months [95% CI, 55.7-64.4]; P = .04). In the mechanical prosthesis group, there was no difference in mean survival between the subgroup with PPM (66.6 months [95% CI, 58.3-74.9]) and the subgroup without PPM (64.9 months [95% CI, 62.6-67.2]; P = .50). A quality-of-life questionnaire's scores did not differ between the groups. CONCLUSION: Mismatch is common after biological valve implantation and statistically significantly affects long-term survival and quality of life. If the risk of PPM after implantation of a biological prosthesis is suspected, adopting strategies to avoid PPM at the time of surgery is warranted.

A combination of two resistance mechanisms is critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody.

Tick-borne encephalitis virus (TBEV) is a flavivirus that causes human neuroinfections and represents a growing health problem. The human monoclonal antibody T025 targets envelope protein domain III (EDIII) of TBEV and related tick-borne flaviviruses, potently neutralizing TBEV in vitro and in preclinical models, representing a promising candidate for clinical development. We demonstrate that TBEV escape in the presence of T025 or T028 (another EDIII-targeting human monoclonal antibody) results in virus variants of reduced pathogenicity, characterized by distinct sets of amino acid changes in EDII and EDIII that are jointly needed to confer resistance. EDIII substitution K311N impairs formation of a salt bridge critical for T025-epitope interaction. EDII substitution E230K is not on the T025 epitope but likely induces quaternary rearrangements of the virus surface because of repulsion of positively charged residues on the adjacent EDI. A combination of T025 and T028 prevents virus escape and improves neutralization.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein.

Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.

The Clinical Impact of the Extension of Acute Type A Aortic Surgery on Long-Term Outcomes: Should We Tend to Be Conservative?

Background and Objectives: Despite advances in surgical techniques, industry adjuncts, and cerebral perfusion techniques, the in-hospital mortality rate of type A acute dissection (TAAD) remains at 15-30%. This study aimed to investigate the influence of different extents of aortic resection on survival and quality of life (QoL) after long-term follow-up. Materials and Methods: A retrospective observational trial was performed, including 165 patients operated upon for TAAD. Patients were divided into two groups according to the extent of their aortic repair: the first group comprised patients who had ascending aorta replacement and the second included patients who had hemiarch or total arch replacement. The groups were compared with regard to their baseline characteristics, operative characteristics, survival, complications, and QoL during nine years of follow-up. Results: The mean follow-up time was 75.6 months (1-108 months). The mean survival in the ascending aorta repair group was 89.651 (81.242-98.061) months and was 54.801 (40.053-69.548) months in the hemiarch and arch group; the difference between the groups was significant (log-rank p < 0.001). The rate of new postoperative neurological deficits was statistically higher in the hemiarch and arch group (17.5% vs. 8.4%, p = 0.045), the most common being stroke, and was also more frequent in the hemiarch and arch group than in the ascending aorta group (with statistical significance (15.7% vs. 6.5%)). The mean SF-12 physical score from the QoL questionnaire was higher in the ascending aorta replacement group than in the hemiarch and arch group (50.1 ± 7.3 vs. 44.0 ± 11.9, p = 0.017). Additionally, the mean SF-12 mental score was higher in the ascending aorta replacement group (52.3 ± 7.3 vs. 47.1 ± 12.8, p = 0.032). Conclusions: A more aggressive approach involving aortic arch repair means a lower survival rate and lesser quality of life after long-term follow-up in comparison with the replacement of the ascending aorta. If clinically applicable, a more defensive strategy may be considered.

Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2.

Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera , including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae , including SARS-CoV-2 variants. One sentence summary: Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course.

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary: Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules.

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

Coronary revascularisation outcome questionnaire: validation study of the Serbian version.

PURPOSE: To translate, culturally adapt and validate the Coronary Revascularisation Outcome Questionnaire (CROQ), a disease-specific tool for measuring health-related quality of life (HRQoL) in patients with ischaemic heart disease (IHD), into Serbian language (CROQ-S). METHODS: Validation study was performed at the Clinic for Cardiac Surgery and Clinic for Cardiology, University Clinical Centre of Serbia. We included a convenience sample of 600 patients with IHD divided into four groups. Acceptability, reliability and validity of the CROQ-S were assessed. RESULTS: CROQ-S was acceptable to patients as demonstrated by less than 1% of missing data for each single item. Cronbach's Alpha was higher than the criterion of 0.70 for all scales in each version except the Cognitive Functioning scale which only met this criterion in the CABG pre-revascularisation version. Mean values of item-total correlations were greater than 0.30 for all scales except the Cognitive Functioning scale in both the pre-revascularisation groups. Compared to the original version, exploratory factor analysis in our study showed more factors; however, the majority of items had a factor loading greater than 0.3 on the right scale. Correlations of CROQ-S scales with the 36-Item Short Form Health Survey and Seattle Angina Questionnaire showed the expected pattern whereby scales measuring similar constructs were most highly correlated. CONCLUSION: CROQ-S is an acceptable, reliable and valid disease-specific instrument for measuring HRQoL in this sample of Serbian speaking patients with IHD both before and after coronary revascularisation. However, the Cognitive Functioning scale did not meet all the psychometric criteria and further validation of its responsiveness is required.

Oxidative Stress in Patients before and after On-Pump and Off-Pump Coronary Artery Bypass Grafting: Relationship with Syntax Score.

OBJECTIVE: Coronary artery bypass grafting (CABG) represents the significant source of increased oxidative stress (OS). We aimed to follow the OS status parameters (i.e., ischemia-modified albumin (IMA), malondialdehyde (MDA), superoxide anion, prooxidant-antioxidant balance (PAB), total oxidant status (TOS), total antioxidant status (TAS), and superoxide-dismutase (SOD)) change through the predefined study times in two different surgical procedures, i.e., cardiopulmonary bypass (CPB) and off-pump coronary artery bypass grafting (OPCAB). Additionally, we aimed to investigate those OS status parameters in specific study times according to SYNTAX score (SS), an established angiographic score for evaluating the extensity and severity of coronary artery disease. Patients and Methods. A total of 107 patients that were planned to undergo CABG were included (i.e., 47 patients in OPCAB and 60 patients in CPB group). Blood samples were taken at 6 time intervals: before surgery (t1), immediately after intervention (t2), 6 h (t3), 24 h (t4), 48 h (t5), and 96 h after termination of the operation (t6). RESULTS: IMA levels were higher in CPB than that in OPCAB baseline and rose in CPB group in t2 point. TOS decreased in both study groups, compared to baseline values, but without statistical significance. Superoxide anion and PAB significantly increased in t3-t6 study times, in both groups. MDA significantly increased only in CPB group in t5 and t6 interval. MDA was significantly higher in CPB group compared to OPCAB in t6 study point. CPB patients had significantly lower TAS compared to OPCAB patients at the beginning and in t2 and t3 study points. They also had significantly lower SOD activities compared to OPCAB, baseline, and in several study points. Moreover, TAS, SOD, and TAS/TOS ratio were significantly lower, whereas PAB and TOS/TAS were significantly higher in patients with high SS compared to corresponding groups. SOD activity, IMA, and TAS level were the best predictors of high SS. CONCLUSION: CPB patients were in more severe ischemia baseline than OPCAB group and IMA rose in CPB patients immediately after the surgery end, but not later. Also, the antioxidant status was significantly lower, whereas the prooxidant status was significantly higher in patients with high SS compared to corresponding groups. SOD activity, IMA, and TAS level were the best predictors of CAD (as determined with SS), showing that SOD and IMA had very good discriminatory capability towards higher SS status.

New Markers of Platelet Activation and Reactivity and Oxidative Stress Parameters in Patients Undergoing Coronary Artery Bypass Grafting.

OBJECTIVE: Recent studies have shown that the red cell distribution width- (RDW-) to-platelet (PLT) count ratio (i.e., RPR) and the mean platelet volume (MPV)/PLT ratio (i.e. MPR) are more sensitive markers of atherosclerosis-connected risk than RDW and PLT alone. The present study is aimed at investigating the oxidative stress status and these two new markers of platelet activation in two different heart surgery modalities: cardiopulmonary bypass (CPB) and off-pump coronary artery bypass (OPCAB). We also aimed to test the possible relationship between RPR and MPR, respectively, and the severity and complexity of atherosclerotic plaque, measured as Syntax Score. Patients and Methods. A total of 107 patients encompassed this prospective study (i.e., 60 patients in CPB group and 47 patients in OPCAB). Blood samples were drawn at several time intervals: before skin incision (t1), immediately after intervention (t2), 6 h (t3), 24 h (t4), 48 h (t5), and 96 h after cessation of the operation (t6). RESULTS: The values of RPR and MPR were similar in CPB and OPCAB before surgery and started to rise in t2 (i.e., immediately after the intervention). This increase lasted to t5 (i.e., 48 hours after the intervention), when it became the highest. After that, both markers started to regress about the 96th hour after the beginning of surgery. Nominal values of both indices were higher in CPB than in OPCAB in all study points after the surgery. Furthermore, a significantly higher level of antioxidative parameters (i.e., total sulfhydryl groups and paraoxonase 1) in the OPCAB group compared to the CPB group was noted at t5 study point (i.e., 48 hours after the surgery), whereas no significant difference was noted in prooxidant levels (i.e., lipid hydroperoxides and advanced oxidation protein products) between these groups at this study point. MPR and RPR correlated positively with Syntax Score at several study points after the surgery completion. Syntax Score, MPR, and RPR showed good clinical accuracy in surgery-related complication prediction ((AUC = 0.736), 95th CI (0.616-0.856), P = 0.003)). CONCLUSION: When combined, MPV, RDW, and platelet count, such as MPR and RPR, could be good predictors of coronary artery disease status, regarding the aspect of joint inflammation, oxidative stress, and thrombosis.

Pulmonary Artery Hypertension as A Risk Factor for Long-Term Survival after Heart Transplantation.

BACKGROUND: Heart failure is the most frequent cause of pulmonary artery hypertension (PAH) and its severity may predict the development of heart failure (HF) and is known to be a prognostic factor of poor outcome after heart transplant (HTx). The aim of this study was to investigate the impact of preoperative PAH related to left-sided HF on long-term survival after HTx and to identify the hemodynamic parameters of PAH that predict survival after HTx. METHODS: A prospective observational trial was performed, and it included 44 patients subjected to heart transplantation. Patients were divided into two groups: The first one with the preoperative diagnosis of PAH and the second one without the PAH diagnosed prior to the HTx. The two groups were compared for baseline characteristics, operative characteristics, survival, and hemodynamic parameters obtained by right heart catheterization. Survival was analyzed using Kaplan Meyer analysis, and Cox regression analysis was performed to determine independent predictors of survival. RESULTS: The median follow-up time was 637.4 days (1-2028 days). The median survival within the group of patients with preoperative PAH was 1144 days (95% CI 662.884-1625.116) and 1918.920 days (95% CI 1594.577-2243.263) within the group of patients without PAH (P = .023), HR 0.279 (95% [CI]: 0.086-0.910; P = .034. The 30-day mortality in patients within PAH group was significantly higher, six versus two patients in the non PAH group (χ2 = 5.103, P < .05), while the long-term outcome after this period did not differ between the groups. Patients with preoperative PAH had significantly higher values of MPAP, PCWP, TPG and PVRI, while CO and CI did not differ between the two groups. Mean PVRI was 359.1 ± 97.3 dyn·s·cm-5 in the group with preoperative PAH and 232.2 ± 22.75 dyn·s·cm-5 in the group without PAH, P < .001. TPG values were 11.95 ± 5.08 mmHg in the PAH group while patients without PAH had mean values of 5.16 ± 1.97 mmHg, P < .001. Cox regression analysis was done for the aforementioned parameters. Hazard ratio for worse survival after HTx for elevated values of PVRI was 1.006 (95% [CI]: 1.001-1.012; P = .018) TPG had a hazard ratio of 1.172 (95% [CI]: 1.032-1.233; P = .015). CONCLUSION: Pulmonary artery hypertension is an independent risk factor for higher 30-day mortality after HTx, while it does not affect the long-term outcome. Hemodynamic parameters obtained by right heart catheterization in heart transplant candidates could predict postoperative outcome. PVRI and TPG have been identified as independent predictors of higher 30-day postoperative mortality.

Machine learning analyses of antibody somatic mutations predict immunoglobulin light chain toxicity.

In systemic light chain amyloidosis (AL), pathogenic monoclonal immunoglobulin light chains (LC) form toxic aggregates and amyloid fibrils in target organs. Prompt diagnosis is crucial to avoid permanent organ damage, but delayed diagnosis is common because symptoms usually appear only after strong organ involvement. Here we present LICTOR, a machine learning approach predicting LC toxicity in AL, based on the distribution of somatic mutations acquired during clonal selection. LICTOR achieves a specificity and a sensitivity of 0.82 and 0.76, respectively, with an area under the receiver operating characteristic curve (AUC) of 0.87. Tested on an independent set of 12 LCs sequences with known clinical phenotypes, LICTOR achieves a prediction accuracy of 83%. Furthermore, we are able to abolish the toxic phenotype of an LC by in silico reverting two germline-specific somatic mutations identified by LICTOR, and by experimentally assessing the loss of in vivo toxicity in a Caenorhabditis elegans model. Therefore, LICTOR represents a promising strategy for AL diagnosis and reducing high mortality rates in AL.

The routine use of platelet function tests in elective coronary artery bypass grafting: A prospective observational trial.

BACKGROUND: Preoperative use of platelet function tests contributes to the decrease of re-intervention rate due to bleeding and the necessity of transfusion in coronary artery bypass grafting (CABG) patients. The aim was to investigate the predictive value and to justify routine preoperative use of multiple electrode aggregometry in these patients. METHODS: A prospective observational trial which included 416 consecutive patients subjected to elective isolated CABG was conducted. The Multiplate® test was used to assess platelet function. Platelet function test results, postoperative blood loss, and transfusion requirements were compared between high and low bleeding risk patients. Receiver operating characteristic analysis was performed to assess the sensitivity and specificity of the arachidonic acid (ASPI) and adenosine di-phosphate high sensitive (ADPHS) tests. RESULTS: ADPHS and ASPI test results significantly predicted total bleeding > 1000 ml (AUC, 0.685, p < .001; 0.695, p = .039). Sensitivity and specificity were 62.9% and 40.0%, for ADPHS ≤602, and 70.8% and 41.8%, for ASPI ≤ 453. The sensitivity and specificity of cut-off values recommended by the manufacturer were 84.2% and 40.0% for ADPHS ≤ 500, while for ASPI < 600 the values were 54.7% and 62.2%. More platelets and cryoprecipitate were transfused in patients with ADPHS ≤ 602.5 (p < .001; p = .035). Patients with ADPHS ≤ 500 had a higher rate of red blood count, platelet and cryoprecipitate transfusion (p<.001p<.001; p = .013). The manufacturer's ASPI test cut-off values showed no statistically significant prediction for a higher transfusion rate. CONCLUSION: Preoperative platelet function tests should be conducted systematically for all elective CABG patients who were on dual antiplatelet therapy after adjusting test cut-off values for each population.

The Prospects of Secondary Moderate Mitral Regurgitation after Aortic Valve Replacement -Meta-Analysis.

Aortic valve replacement for aortic stenosis represents one of the most frequent surgical procedures on heart valves. These patients often have concomitant mitral regurgitation. To reveal whether the moderate mitral regurgitation will improve after aortic valve replacement alone, we performed a systematic review and meta-analysis. We identified 27 studies with 4452 patients that underwent aortic valve replacement for aortic stenosis and had co-existent mitral regurgitation. Primary end point was the impact of aortic valve replacement on the concomitant mitral regurgitation. Secondary end points were the analysis of the left ventricle reverse remodeling and long-term survival. Our results showed that there was significant improvement in mitral regurgitation postoperatively (RR, 1.65; 95% CI 1.36-2.00; p < 0.00001) with the average decrease of 0.46 (WMD; 95% CI 0.35-0.57; p < 0.00001). The effect is more pronounced in the elderly population. Perioperative mortality was higher (p < 0.0001) and long-term survival significantly worse (p < 0.00001) in patients that had moderate/severe mitral regurgitation preoperatively. We conclude that after aortic valve replacement alone there are fair chances but for only slight improvement in concomitant mitral regurgitation. The secondary moderate mitral regurgitation should be addressed at the time of aortic valve replacement. A more conservative approach should be followed for elderly and high-risk patients.

Successfully Resected Cardiac Metastatic Melanoma in a Lifesaving Cardiac Surgery: A Case Report.

INTRODUCTION: Metastatic tumors are the most frequent tumors of the heart with the melanoma metastasis being the most frequent. In cases of a cardiac tamponade or a low cardiac output syndrome due to the position of the tumor it could lead to an acute life-threatening condition for the patient. CASE REPORT: We present a case of a successfully treated metastatic cardiac melanoma in a lifesaving cardiac surgery. A 42-year-old woman was admitted to the emergency department of the Clinical Center of Serbia in a critical state with signs of tricuspid orifice obstruction with a tumor mass. Her previous medical history showed that she had an adequate surgical excision of the melanoma in the right lumbar region at the age of 39. An emergency cardiac surgery was performed with the resection of the tumor and the atrial wall. The postoperative course was uneventful and a HP exam once again confirmed the same type of melanoma as previously diagnosed. The patient was alive and well on follow-up exams for 4 months when she was diagnosed with metastatic tumor masses in the pelvis with ascites and melanosis of the entire skin followed by lethal outcome 5 months after the cardiac surgery. CONCLUSION: Surgical resection of metastatic cardiac melanoma can be safe and effective in an emergency scenario, especially in the case of solitary metastasis. It can be performed with excellent results and very few postoperative complications. However, due to the nature of the principal disease, the long-term survival rate remains low, giving the surgery a place in palliative treatment.

Long Term Outcomes of The Off-Pump and On-Pump Coronary Artery Bypass Grafting In A High-Volume Center.

Coronary artery bypass grafting (CABG) remains the most frequent surgery in the practice of an adult cardiac surgeon and the most frequently performed cardiac surgical procedure worldwide. Despite the ongoing debates regarding the superiority or inferiority of off-pump coronary artery bypass grafting, it still comprises 15-30% of all CABG cases varying in different national registries. We performed a propensity matched study of 302 consecutive CABG patients,143 off -pump cases performed by the four experienced off-pump surgeons and the on-pump CABG cases performed by those surgeons and four other experienced coronary surgeons. The five year follow up was performed and data collected comprised of mortality, rehospitalization due to cardiac origin, repeated revascularization, myocardial infarction and cerebrovascular accident. Overall, the off-pump group of patients had a higher risk profile than the patients in the on-pump group. After matching, fewer differences were found between the groups. Propensity score matching analysis showed no difference in long-term survival as well as MACCE and repeated revascularization. The higher risk profile of the patients subjected to OPCAB and the comparable survival to lower risk CPB patients in this series indicate that in experienced hands, OPCAB is a valuable option in this important subgroup of patients.

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development.

Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific "signal transducer and activator of transcription" (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.

Structural role of the T94I rhodopsin mutation in congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited and non-progressive retinal dysfunction. Here, we present the crystal structure of CSNB-causing T94I2.61 rhodopsin in the active conformation at 2.3 Å resolution. The introduced hydrophobic side chain prolongs the lifetime of the G protein activating metarhodopsin-II state by establishing a direct van der Waals contact with K2967.43, the site of retinal attachment. This is in stark contrast to the light-activated state of the CSNB-causing G90D2.57 mutation, where the charged mutation forms a salt bridge with K2967.43 To find the common denominator between these two functional modifications, we combined our structural data with a kinetic biochemical analysis and molecular dynamics simulations. Our results indicate that both the charged G90D2.57 and the hydrophobic T94I2.61 mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E1133.28 We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients.