Gene expression and in vitro replication of bovine gammaherpesvirus type 4.

In vitro cell cultures are widely used models for dissecting cellular and molecular mechanisms that lead to certain physiological conditions and diseases. The pathogenesis of BoHV-4 in the bovine reproductive tract has been studied by conducting tests on primary cultures. However, many questions remain to be answered about the role of BoHV-4 in endometrial cells. The aim of this study was to compare the replication and gene expression of BoHV-4 in cell lines and bovine reproductive tract primary cells as an in vitro model for the study of this virus. We demonstrated that BoHV-4 strains differ in their in vitro growth kinetics and gene expression but have the same cell type preference. Our results demonstrate that BoHV-4 replicates preferentially in bovine endometrial cells (BEC). However, its replication capacity extends to various cell types, since all cells that were tested were permissive to BoHV-4 infection. The highest virus titers were obtained in BEC cells. Nevertheless, virus replication efficiency could not be fully predicted from the mRNA expression profiles. This implies that there are multiple cell-type-dependent factors and strain properties that determine the level of BoHV-4 replication. The results of this study provide relevant information about the in vitro behavior of two field isolates of BoHV-4 in different cell cultures. These findings may be useful for the design of future in vitro experiments to obtain reliable results not only about the pathogenic role of BoHV-4 in the bovine female reproductive tract but also in the development of efficient antiviral strategies.

Recycling agricultural, municipal and industrial pollutant wastes into fertilizers for a sustainable healthy food production.

This work was focused on recycling different typology of pollutant wastes (olive pomace and orange residues; municipal wastes and sulphur residue of hydrocarbon refining processes) with the triple objectives of limiting wastes in landfill, reducing greenhouse gas emission and producing organic-mineral fertilizers. The environmental risks and benefits of the whole process have been considered. The specific objectives were: 1) innovation in waste management techniques by reducing the accumulation of different typology of wastes using a unique process 2) verifying efficiency of the obtained organic-mineral fertilizers on soil and plant growth 3) improving soil and crop quality relating wastes to food, economy and environment. Sulphur-based pads improved soil quality mostly when contained orange residues. Onion and Garlic grew better in presence of sulphur-based pads (+20%), and mostly when pads contained orange residues (+45%). Onion and Garlic quality, in terms of antioxidant compounds and antioxidant capacity, increased in presence of sulphur-based pads (+30%) mostly when orange residues were present in the pads (+90%). In short, in addition to the environmental advantages, numerous economic benefits coming from the decrease in the production and use of chemical fertilizers, the reduction of costs for landfilling and the gain rising from the sale of the new fertilizers produced, emerged.

Pancreaticoduodenectomy for paraduodenal pancreatitis is associated with a higher incidence of diabetes but a similar quality of life and pain control when compared to medical treatment.

BACKGROUND: Paraduodenal pancreatitis is a focal form of chronic pancreatitis that affects the groove area between the duodenum and the head of the pancreas. Consensus regarding surgical or nonsurgical management as the best treatment option is still lacking. METHODS: We retrospectively evaluated all patients managed for PP at The Pancreas Institute of the University Hospital Trust of Verona from 1990 to 2017. The outcomes of surgical vs. medical treatment with regard to pain control, quality of life and pancreatic insufficiency were evaluated through specific questionnaires. RESULTS: The final study population consisted of 75 patients: 62.6% underwent surgery, and 37.4% were managed without surgery. All surgical procedures consisted of pancreaticoduodenectomy. The median follow-up from the diagnosis of paraduodenal pancreatitis was 60 (12-240) months. Patients who underwent surgery experienced a similar incidence of steatorrhea (44.7 vs. 52.6%; p = 0.4) but a significantly higher incidence of diabetes (59.6 vs. 10.7%; p < 0.01) when compared to those managed without surgery. There was no difference in terms of reported chronic pain (Graded Chronic Pain Scale, median 0 vs. 1; p = 0.1) and quality of life (Pancreatitis QoL Instrument, median 82 vs. 79; p = 0.2). However, surgical patients reported a worse level of self-care activities associated with glycemic control (Diabetes Self-Management Questionnaire, median 20 vs. 28, p = 0.02). CONCLUSION: In patients affected by paraduodenal pancreatitis, surgery and medical therapy seem to obtain similar results in terms of quality of life and pain control. However, surgery is associated with an increased prevalence of postoperative diabetes with consequent relevant issues with self-care management. Surgery should be considered only in selected patients after adequate medical treatment.

The Von Willebrand Factor Antigen Plasma Concentration: a Monitoring Marker in the Treatment of Aortic and Mitral Valve Diseases.

Von Willebrand disease is a commonly inherited bleeding disorder caused by defects of von Willebrand factor (vWF). In the most common valve diseases, aortic valve stenosis (AVS) and mitral valve regurgitation (MVR), a bleeding tendency has been described in a number of patients. This has been associated to a high turbulence of blood flow through the compromised valve, promoting degradation of vWF with loss of high-molecular-weight multimers of vWF (HMWM), leading to an acquired von Willebrand syndrome (AvWS). We analysed three groups of patients, one affected by AVS, treated with transcatheter aortic valve implantation (TAVI), the second group of patients affected by MVR, treated with Mitraclip® mitral valve repair. The third group was represented by patients also affected by AVS, but not eligible for TAVI and treated with standard surgery. A fourth group of patients that underwent percutaneous coronary intervention (PCI) with stenting was used as a control. Our results demonstrated that the level of vWF measured as antigen concentration (vWF:Ag) increases in all cohorts of patients after treatment, while in control PCI patients, no modification of vWF:Ag has been registered. Western blot analysis showed only a quantitative loss of vWF in the pre-treatment time, but without significant HMWM modification. The monitoring of the vWF:Ag concentration, but not the quality of HMWM, can indicate the status of blood flow in the treated patients, thus introducing the possibility of using the vWF antigen detection in monitoring the status of replaced or repaired valves.

Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study.

PURPOSE: Proper evaluation of polyphenols intake at the population level is a necessary step in order to establish possible associations with health outcomes. Available data are limited, and so far no study has been performed in people with diabetes. The aim of this work was to document the intake of polyphenols and their major food sources in a cohort of people with type 2 diabetes and in socio-demographic subgroups. METHODS: We studied 2573 men and women aged 50-75 years. Among others, anthropometry was measured by standard protocol and dietary habits were investigated by food frequency questionnaire (EPIC). The intake of polyphenols was evaluated using US Department of Agriculture and Phenol-Explorer databases. RESULTS: The mean total polyphenol intake was 683.3 ± 5.8 mg/day. Non-alcoholic beverages represented the main food source of dietary polyphenols and provided 35.5% of total polyphenol intake, followed by fruits (23.0%), alcoholic beverages (14.0%), vegetables (12.4%), cereal products and tubers (4.6%), legumes (3.7%) and oils (2.1%); chocolate, cakes and nuts are negligible sources of polyphenols in this cohort. The two most important polyphenol classes contributing to the total intake were flavonoids (47.5%) and phenolic acids (47.4%). Polyphenol intake increased with age and education level and decreased with BMI; furthermore, in the northern regions of Italy, the polyphenol intake was slightly, but significantly higher than in the central or southern regions. CONCLUSIONS: The study documents for the first time the intake of polyphenols and their main food sources in people with diabetes using validated and complete databases of the polyphenol content of food. Compared with published data, collected in people without diabetes, these results suggest a lower intake and a different pattern of intake in people with diabetes.

Healthcare resource use, direct and indirect costs of hypoglycemia in type 1 and type 2 diabetes, and nationwide projections. Results of the HYPOS-1 study.

BACKGROUND AND AIMS: To obtain an accurate picture of the total costs of hypoglycemia, including the indirect costs and comparing the differences between type 1 (T1DM) and type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: HYPOS-1 was a multicenter, retrospective cohort study which analyzed the data of 2229 consecutive patients seen at 18 diabetes clinics. Data on healthcare resource use and indirect costs by diabetes type were collected via a questionnaire. The domains of inpatient admission and hospital stay, work days lost, and third-party assistance were also explored. Resource utilization was reported as estimated incidence rates (IRs) of hypoglycemic episodes per 100 person-years and estimated costs as IRs per person-years. For every 100 patients with T1DM, 9 emergency room (ER) visits and 6 emergency medical service calls for hypoglycemia were required per year; for every 100 patients with T2DM, 3 ER visits and 1 inpatient admission were required, with over 3 nights spent in hospital. Hypoglycemia led to 58 work days per 100 person-years lost by the patient or a family member in T1DM versus 19 in T2DM. The costs in T1DM totaled €90.99 per person-year and €62.04 in T2DM. Direct and indirect costs making up the total differed by type of diabetes (60% indirect costs in T1DM versus 43% in T2DM). The total cost associated with hypoglycemia in Italy is estimated to be €107 million per year. CONCLUSIONS: Indirect costs meaningfully contribute to the total costs associated with hypoglycemia. As compared with T1DM, T2DM requires fewer ER visits and incurs lower indirect costs but more frequent hospital use.

Deep sternal wound infections: a severe complication after cardiac surgery.

Sternal Wound Infections (SWI) represent a dangerous complication after cardiac surgery entailing significantly longer hospital stays and worse short-term survival, especially in case of deep infections (DSWI) with the onset of osteomielitis or mediastinitis. The real incidence of SWI can be estimated between 0.25% and 10%; among the risk factors for sternal dehiscences after a longitudinal median sternotomy, several experiences underline the role of diabetes as an independent risk factor for post-operative infections, especially in patients affected by COPD with higher BMI. The application of a negative-pressure therapy, through instill modality too, assures a wound cleansing through periodic irrigation of topical solutions with particulate secretion removal; moreover it improves the granulation process owing to the increased blood flow and makes the size wound reduction easier, representing very often the treatment of first-line in DSWI and an optimal bridge for another reconstructive procedure of the sternal defect. The following case report shows how a plastic surgical approach associated to the adoption of a VAC-therapy instill after specific antibiotictherapy has integrated and optimized the trend of a very complex clinical circumstance.

Influence of dietary fat and carbohydrates proportions on plasma lipids, glucose control and low-grade inflammation in patients with type 2 diabetes-The TOSCA.IT Study.

PURPOSE: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors. METHODS: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured. RESULTS: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake. CONCLUSIONS: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

Transient and chaotic low-energy transfers in a system with bistable nonlinearity.

The low-energy dynamics of a two-dof system composed of a grounded linear oscillator coupled to a lightweight mass by means of a spring with both cubic nonlinear and negative linear components is investigated. The mechanisms leading to intense energy exchanges between the linear oscillator, excited by a low-energy impulse, and the nonlinear attachment are addressed. For lightly damped systems, it is shown that two main mechanisms arise: Aperiodic alternating in-well and cross-well oscillations of the nonlinear attachment, and secondary nonlinear beats occurring once the dynamics evolves solely in-well. The description of the former dissipative phenomenon is provided in a two-dimensional projection of the phase space, where transitions between in-well and cross-well oscillations are associated with sequences of crossings across a pseudo-separatrix. Whereas the second mechanism is described in terms of secondary limiting phase trajectories of the nonlinear attachment under certain resonance conditions. The analytical treatment of the two aformentioned low-energy transfer mechanisms relies on the reduction of the nonlinear dynamics and consequent analysis of the reduced dynamics by asymptotic techniques. Direct numerical simulations fully validate our analytical predictions.

Feasibility and accuracy of the screening for diabetic retinopathy using a fundus camera and an artificial intelligence pre-evaluation application.

AIMS: Periodical screening for diabetic retinopathy (DR) by an ophthalmologist is expensive and demanding. Automated DR image evaluation with Artificial Intelligence tools may represent a clinical and cost-effective alternative for the detection of retinopathy. We aimed to evaluate the accuracy and reliability of a machine learning algorithm. METHODS: This was an observational diagnostic precision study that compared human grader classification with that of DAIRET®, an algorithm nested in an electronic medical record powered by Retmarker SA. Retinal images were taken from 637 consecutive patients attending a routine annual diabetic visit between June 2021 and February 2023. They were manually graded by an ophthalmologist following the International Clinical Diabetic Retinopathy Severity Scale and the results were compared with those of the AI responses. The main outcome measures were screening performance, such as sensitivity and specificity and diagnostic accuracy by 95% confidence intervals. RESULTS: The rate of cases classified as ungradable was 1.2%, a figure consistent with the literature. DAIRET® sensitivity in the detection of cases of referable DR (moderate and above, "sight-threatening" forms of retinopathy) was equal to 1 (100%). The specificity, that is the true negative rate of absence of DR, was 80 ± 0.04. CONCLUSIONS: DAIRET® achieved excellent sensitivity for referable retinopathy compared with that of human graders. This is undoubtedly the key finding of the study and translates into the certainty that no patient in need of the ophthalmologist is misdiagnosed as negative. It also had sufficient specificity to represent a cost-effective alternative to manual grade alone.

Diabetic retinopathy screening with confocal fundus camera and artificial intelligence - assisted grading.

PURPOSE: Screening for diabetic retinopathy (DR) by ophthalmologists is costly and labour-intensive. Artificial Intelligence (AI) for automated DR detection could be a clinically and economically alternative. We assessed the performance of a confocal fundus imaging system (DRSplus, Centervue SpA), coupled with an AI algorithm (RetCAD, Thirona B.V.) in a real-world setting. METHODS: 45° non-mydriatic retinal images from 506 patients with diabetes were graded both by an ophthalmologist and by the AI algorithm, according to the International Clinical Diabetic Retinopathy severity scale. Less than moderate retinopathy (DR scores 0, 1) was defined as non-referable, while more severe stages were defined as referable retinopathy. The gradings were then compared both at eye-level and patient-level. Key metrics included sensitivity, specificity all measured with a 95% Confidence Interval. RESULTS: The percentage of ungradable eyes according to the AI was 2.58%. The performances of the AI algorithm for detecting referable DR were 97.18% sensitivity, 93.73% specificity at eye-level and 98.70% sensitivity and 91.06% specificity at patient-level. CONCLUSIONS: DRSplus paired with RetCAD represents a reliable DR screening solution in a real-world setting. The high sensitivity of the system ensures that almost all patients requiring medical attention for DR are referred to an ophthalmologist for further evaluation.

Cooper pairs spintronics in triplet spin valves.

We study a spin valve with a triplet superconductor spacer intercalated between two ferromagnets with noncollinear magnetizations. We show that the magnetoresistance of the triplet spin valve depends on the relative orientations of the d vector, characterizing the superconducting order parameter, and the magnetization directions of the ferromagnetic layers. For devices characterized by a long superconductor, the effects of a polarized current sustained by Cooper pairs only are observed. In this regime, a supermagnetoresistance effect emerges, and the chiral symmetry of the order parameter of the superconducting spacer is easily recognized. Our findings open new perspectives in designing spintronics devices based on the cooperation of ferromagnetic and triplet correlations.

Efficacy of cefiderocol- vs colistin-containing regimen for treatment of bacteraemic ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii in patients with COVID-19.

INTRODUCTION: Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) in patients hospitalized in intensive care units (ICUs) is an important and challenging complication, including in patients with coronavirus disease 2019 (COVID-19). Considering the poor lung penetration of most antibiotics, including intravenous colistin due to the poor pharmacokinetics/pharmacodynamics at the infection site, the choice of the best antibiotic regimen is still being debated. METHODS: This single-centre, observational study was conducted from March 2020 to August 2022, and included all patients hospitalized consecutively with VAP and concomitant bloodstream infection due to CRAB in the COVID-ICU. The main goal of the study was to evaluate risk factors associated with survival or death at 30 days from VAP onset. A propensity score for receiving therapy was added to the model. RESULTS: During the study period, 73 patients who developed VAP and concomitant positive blood cultures caused by CRAB were enrolled in the COVID-ICU. Of these patients, 67 (91.7%) developed septic shock, 42 (57.5%) had died at 14 days and 59 (80.8%) had died at 30 days. Overall, 54 (74%) patients were treated with a colistin-containing regimen and 19 (26%) were treated with a cefiderocol-containing regimen. Cox regression analysis showed that chronic obstructive pulmonary disease and age were independently associated with 30-day mortality. Conversely, cefiderocol-containing regimens and cefiderocol + fosfomycin in combination were independently associated with 30-day survival, as confirmed by propensity score analysis. CONCLUSIONS: This real-life study in patients with bacteraemic VAP caused by CRAB provides useful suggestions for clinicians, showing a possible benefit of cefiderocol and its association with fosfomycin.

Safety of cold polypectomy for <10mm polyps at colonoscopy: a prospective multicenter study.

BACKGROUND: Cold polypectomy techniques (without electrocautery) by means of biopsy forceps or snare are widely adopted for the removal of subcentimetric polyps. However, few data are available on the safety of this approach. The aim of this study was to assess the safety of cold polypectomy for subcentimetric polyps, as well as the rate of advanced neoplasia in these lesions. PATIENTS AND METHODS: In a prospective multicenter trial, consecutive patients with at least one < 10-mm polyp at colonoscopy were prospectively included. All of the < 10-mm polyps detected within the study period were removed by cold polypectomy. The rates of immediate or delayed bleeding and other complications were assessed at 7 and 30 days after cold polypectomy by telephone calls. The rate of advanced histology was also assessed. Predictive variables of postpolypectomy bleeding or advanced neoplasia were identified by multivariate analysis. RESULTS: A total of 1015 < 10-mm polyps in 823 patients (15.5 % on antiplatelet agents) were removed. Of these, 822 (81 %) were ≤ 5 mm and 193 (19 %) were 6 - 9 mm. Immediate postpolypectomy bleeding occurred in 18 patients, corresponding to a per-patient and per-polyp bleeding rate of 2.2 % (95 % confidence interval [CI] 1.2 % - 3.2 %) and 1.8 % (95 %CI 1 % - 2.6 %), respectively. Therapy with antiplatelet agents (odds ratio [OR] 4; 95 %CI 1.5 - 10.6) and larger polyp size (OR 2; 95 %CI 1.1 - 6.9) were independent predictors of bleeding. Bleeding was successfully treated by endoscopic hemostasis in all cases and required no further medical intervention. Advanced neoplasia prevalence in polyps ≤ 5 mm was as high as 8.7 %. CONCLUSIONS: The results from this study showed the high safety of a cold polypectomy approach for subcentimetric polyps. This was due to the low rate of postpolypectomy bleeding and to the high efficacy of endoscopic hemostasis in its treatment. The high rate of advanced neoplasia in polyps ≤ 5 mm should prompt some caution on the management of these lesions following detection at computed tomography colonography or colon capsule endoscopy.

Antithrombotic therapy management in a man with ST elevation myocardial infarction and triple positive antiphospholipid syndrome: case report and literature review.

OBJECTIVE: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder associated with vascular complications including acute myocardial infarction (AMI). AMI pathogenesis in APS is considered to be acute thrombosis of coronary arteries, in contrast to typical AMI where the pathogenesis is atherosclerotic plaque rupture. Therapeutic management is therefore a clinical challenge. There is no consensus among experts about optimal antithrombotic therapy in secondary prevention. The role of coronary stents is still to be determined, due to the higher rates of stent thrombosis after percutaneous coronary intervention (PCI) in APS patients. CASE REPORT: We described the case of a 51-year-old male, smoker, that presented with anterior ST elevation myocardial infarction (STEMI) as first manifestation of APS. The patient underwent primary PCI on left main and ostial left anterior descending artery. RESULTS: We discussed antithrombotic therapy management after PCI in our patient and reviewed literature on current therapeutic management of this specific population. CONCLUSIONS: APS patients with STEMI should undergo PCI, usually associated with thrombus aspiration, and in select cases stent implantation in the culprit lesion. In the latter case, triple antithrombotic therapy with short-term dual antiplatelet therapy and long-term anticoagulant therapy is recommended. Clinicians should include autoimmune etiologies in the differential diagnosis of underlying causes of AMI.

Local gentamicin-collagen sponge reduces cardiovascular implantable electronic device infections and pocket hematoma.

OBJECTIVE: Implantation or replacement of a cardiovascular implantable electronic device (CIED) may be associated with complications, such as pocket hematomas and infections. This study aims to determine whether a lyophilized gentamycin-containing collagen implant (GCCI) reduces major CIED infections and pocket hematomas after implant. SUBJECTS AND METHODS: A retrospective study was conducted among patients who underwent implantation or replacement of CIED at the Tor Vergata Polyclinic (Rome, Italy) between June 2007 and November 2019. The primary combined endpoint was infection and hematoma occurrence through 12 months of follow-up post-procedure. The rate of single infectious complications, pocket hematomas or both were also assessed. RESULTS: We compared 475 patients treated with the GCCI (GCCI group) with 714 patients who did not receive it (control group). Complications occurred in 127 patients (11%); a statistically significant reduction of infections and pocket hematomas in the GCCI group was reported when compared with control patients (1% vs. 17%; p<0.0001). A total of 20 (2%) infectious events were reported, 102 (8%) patients developed a pocket hematoma, and 5 (0.4%) had both. The rate of single complications was significantly lower in GCCI group: infection 0.2% vs. 2.6% (p=0.002), pocket hematoma 0.6% vs. 13.8% (p<0.001). The association between antiplatelet/anticoagulation therapy and hematoma development was not statistically significant. CONCLUSIONS: The GCCI is a medical device that can be used in addition to local hemostasis and prophylactic doses of systemic antibiotics with the aim of reducing infective complications and pocket hematoma after permanent CIED implantation or replacement.

Target-controlled infusion during MitraClip procedures in deep-sedation with spontaneous breathing.

OBJECTIVE: Percutaneous mitral valve repair with the MitraClip system is an alternative procedure for high-risk patients not suitable for conventional surgery. The MitraClip can be safely performed under general anesthesia (GA) or deep sedation (DS) with spontaneous breathing using a combination of propofol and remifentanil. This study aimed to evaluate the benefits of target-controlled infusion (TCI) of remifentanil and administration of propofol during DS compared with manual administration of total intravenous anesthesia (TIVA) medication during GA in patients undergoing MitraClip. We assessed the impact of these procedures in terms of remifentanil dose, hemodynamic profile, adverse events, and days of hospital stay after the process. PATIENTS AND METHODS: From March 2013 to June 2015 (mean age 73.5 ± 9,54), patients underwent transcatheter MitraClip repair, 27 received DS via TCI and 27 GA with TIVA. RESULTS: Acute procedural success was 100%. DS-TCI group, in addition to a significant reduction of remifentanil dose administrated (249 µg vs. 2865, p < 0.01), resulted in a decrease in vasopressor drugs requirement for hemodynamic adjustments (29.6% vs. 63%, p = 0.03) during the procedure and a reduction of hypotension (p = 0.08). The duration of postoperative hospitalization did not differ between the two groups (5.4 days vs. 5.8 days, p = 0.4). CONCLUSIONS: Administration of remifentanil by TCI for DS in spontaneously breathing patients offers stable anesthesia conditions, with a lower amount of drugs, higher hemodynamic stability, and decreased side effects.

CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.

Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.

Excimer laser technology in percutaneous coronary interventions: Cardiovascular laser society's position paper.

Excimer Laser Coronary Atherectomy (ELCA) is a well-established therapy that emerged for the treatment of peripheral vascular atherosclerosis in the late 1980s, at a time when catheters and materials were rudimentary and associated with the most serious complications. Refinements in catheter technology and the introduction of improved laser techniques have led to their effective use for the treatment of a wide spectrum of complex coronary lesions, such as thrombotic lesions, severe calcific lesions, non-crossable or non-expandable lesions, chronic occlusions, and stent under-expansion. The gradual introduction of high-energy strategies combined with the contrast infusion technique has enabled us to treat an increasing number of complex cases with a low rate of periprocedural complications. Currently, the use of the ELCA has also been demonstrated to be effective in acute coronary syndrome (ACS), especially in the context of large thrombotic lesions.

Changes in brain natriuretic peptide level as a predictor of AF recurrence after electrical cardioversion.

AIM: Early recurrence of atrial fibrillation (AF) is common after electrical cardioversion (ECV). Accurate prediction of AF recurrence might allow more selective use of ECV and the targeted use of antiarrhtyhmic therapy in those at highest risk of recurrence. METHODS: We have screened consecutive patients attending for cardioversion of AF and recruited those without valvular heart disease, heart failure or permanent pacemakers. All patients underwent echocardiography and measurement of serum BNP levels within 24 hours before ECV. Measurement of BNP was repeated at 1, 7, 30 and 90 days after ECV and an ECG recorded on each occasion. RESULTS: We have screened 24 consecutive patients. Five were excluded. All 19 study subjects were succesfully cardioverted to sinus rhythm. AF recurred in nine cases. Recurrence of AF was associated with AF duration, left atrial size, the presence of hypertension and the BNP level before cardioversion. BNP fell significantly after cardioversion. The BNP level after cardioversion was not associated with AF recurrence. CONCLUSION: Even in persons without valvular heart disease or heart failure, an elevated level of BNP predicts recurrence of AF after ECV. The level to which BNP falls after cardioversion is not predictive of AF recurrence.