A key GPCR phosphorylation motif discovered in arrestin2⋠CCR5 phosphopeptide complexes.

The two non-visual arrestins, arrestin2 and arrestin3, bind hundreds of GPCRs with different phosphorylation patterns, leading to distinct functional outcomes. Structural information on these interactions is available only for very few GPCRs. Here, we have characterized the interactions between the phosphorylated human CC chemokine receptor 5 (CCR5) and arrestin2. We identified several new CCR5 phosphorylation sites necessary for stable arrestin2 complex formation. Structures of arrestin2 in the apo form and complexes with CCR5 C-terminal phosphopeptides, together with NMR, biochemical, and functional assays, revealed three phosphoresidues in a pXpp motif that are essential for arrestin2 binding and activation. The identified motif appears responsible for robust arrestin2 recruitment in many other GPCRs. An analysis of receptor sequences and available structural and functional information provides hints on the molecular basis of arrestin2/arrestin3 isoform specificity. Our findings demonstrate how multi-site phosphorylation controls GPCR⋅arrestin interactions and provide a framework to probe the intricate details of arrestin signaling.

In vitro activity of imipenem/relebactam and ceftazidime/avibactam against carbapenem-resistant Klebsiella pneumoniae from blood cultures in a University hospital in Serbia.

The study aimed to investigate prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) blood culture isolates and their susceptibility to two new antibiotics, imipenem/relebactam and ceftazidime/avibactam. Out of 765 isolates recovered from blood cultures in a tertiary care hospital in Serbia between 2020 and 2023, 143 non-repetitive K. pneumoniae strains were included in this study. Minimum inhibitory concentration (MIC) values of the examined antimicrobial drugs was determined by VITEK 2 system, MIC test strip (imipenem/relebactam and ceftazidime/avibactam), and broth microdilution method (tigecycline and colistin). Carbapenemase-encoding genes (blaKPC, blaOXA-48-like, blaNDM, blaVIM, blaIMP) were detected using a multiplex-PCR assay, the BioFire-Blood Culture Identification 2-panel. This closed molecular assay is designed for the BioFire® FilmArray® system, enabling automated sample preparation, amplification, detection, and analysis (bioMérieux, France). Results revealed that K. pneumoniae was the most common isolate from blood cultures in 2022. The prevalence of K. pneumoniae was about 11.6% in 2020 and 2021, while in 2022 it raised to over 30%. Also, the frequency of CRKP increased from 11.76% in 2020, through 15.29% in 2021 to 72.94% in 2022. The majority of CRKP carried blaOXA-48-like (60.0%), followed by blaKPC (16.47%), and blaNDM (8.24%) genes, while 14.12% harboured both blaOXA-48-like and blaNDM genes. Only 25.88% of CRKP isolates were resistant to ceftazidime/avibactam, while 51.76% were resistant to imipenem/relebactam and colistin. The rapid spread of CRKP is particularly concerning because therapeutic options are limited to a few antibiotics. While imipenem/relebactam and colistin showed similar antimicrobial activity against CRKP clinical isolates, ceftazidime/avibactam proved to be the most effective antibiotic.

Alternating or Bilateral Exercise Training does not Influence Force Control during Single-Leg Submaximal Contractions with the Dorsiflexors.

The aim of the study was to assess the influence of habitual training history on force steadiness and the discharge characteristics of motor units in tibialis anterior during submaximal isometric contractions. Fifteen athletes whose training emphasized alternating actions (11 runners and 4 cyclists) and fifteen athletes who relied on bilateral actions with leg muscles (7 volleyball players, 8 weight-lifters) performed 2 maximal voluntary contractions (MVC) with the dorsiflexors, and 3 steady contractions at 8 target forces (2.5%, 5%, 10%, 20%, 30%, 40%, 50% and 60% MVC). The discharge characteristics of motor units in tibialis anterior were recorded using high-density electromyography grids. The MVC force and the absolute (standard deviation) and normalized (coefficient of variation) amplitudes of the force fluctuations at all target forces were similar between groups. The coefficient of variation for force decreased progressively from 2.5% to 20% MVC force, then it plateaued until 60% MVC force. Mean discharge rate of the motor units in tibialis anterior was similar at all target forces between groups. The variability in discharge times (coefficient of variation for interspike interval) and the variability in neural drive (coefficient of variation of filtered cumulative spike train) was also similar for the two groups. These results indicate that athletes who have trained with either alternating or bilateral actions with leg muscles has similar effects on maximal force, force control, and variability in the independent and common synaptic input during a single-limb isometric task with the dorsiflexors.

Biomagnetic Priming-Possible Strategy to Revitalize Old Mustard Seeds.

Different priming methods were developed to improve seed germination and the early growth of seedlings. This study aimed to examine the combined effect of bacterial inoculation and static magnetic field on white mustard (Sinapis alba L.) germination. A plant growth-promoting bacterial strain Bacillus amyloliquefaciens D5 ARV was used for biopriming. The static magnetic field of 90 mT was applied for 5 and 15 min. Analyses of abscisic acid, chlorophyll, anthocyanins, flavonoids content, nitrogen balance index, and bacterial indole-3-acetic acid were used to explain observed effects. Bacterial inoculation improved seed germination, whereas exposure to 90 mT for 15 min suppressed germination. Such an unfavorable effect was neutralized when the treatment with the static magnetic field was combined with bacterial inoculation. The highest germination percentage was a result of synergistic action of B. amyloliquefaciens D5 ARV and 15 min long exposure to 90 mT, which induced an increase of 53.20% in the number of germinated seeds. The static magnetic field induced the increase of bacterial indole-3-acetic acid production threefold times. Biomagnetic priming caused a metabolic shift from primary to secondary metabolism in the white mustard seedlings. An adequate combination of biological priming and static magnetic field treatment can be successfully used in old seed revitalization and germination improvements. © 2021 Bioelectromagnetics Society.

Effect of long-term drought on tomato leaves: the impact on metabolic and antioxidative response.

Water deficit triggers physiological, biochemical, and molecular changes in leaves that could be important for overall plant adaptive response and it can affect tomato yield and quality. To assess the influence of long-term moderate drought on leaves, four tomato accessions from MAGIC TOM populations were selected on the basis of their differences in fruit size and were grown in a glasshouse under control and water deficit conditions. Drought affected stomatal conductance more in large fruit genotypes compared to cherry genotypes and this could be related to higher abscisic acid (ABA) leaf content. Compared to large fruits, cherry tomato genotypes coped better with water stress by reducing leaf area and maintaining photochemical efficiency as important adaptive responses. Accumulation of soluble sugars in the cherry genotypes and organic acid in the leaves of the larger fruit genotypes indicated their role in the osmoregulation and the continuum of source/sink gradient under stress conditions. Long-term moderate drought induced upregulation of NCED gene in all four genotypes that was associated with ABA production. The increase in the expression of ZEP gene was found only in the LA1420 cherry genotype and indicated its possible role in the protection against photooxidative stress induced by prolonged water stress. In addition, upregulation of the APX genes, higher accumulation of vitamin C and total antioxidant capacity in cherry genotype leaves highlighted their greater adaptive response against long-term drought stress compared to larger fruit genotypes that could also reflect at fruit level. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01102-2.

Microprocessor-dependent processing of splice site overlapping microRNA exons does not result in changes in alternative splicing.

MicroRNAs are found throughout the genome and are processed by the microprocessor complex (MPC) from longer precursors. Some precursor miRNAs overlap intron:exon junctions. These splice site overlapping microRNAs (SO-miRNAs) are mostly located in coding genes. It has been intimated, in the rarer examples of SO-miRNAs in noncoding RNAs, that the competition between the spliceosome and the MPC modulates alternative splicing. However, the effect of this overlap on coding transcripts is unknown. Unexpectedly, we show that neither Drosha silencing nor SF3b1 silencing changed the inclusion ratio of SO-miRNA exons. Two SO-miRNAs, located in genes that code for basal membrane proteins, are known to inhibit proliferation in primary keratinocytes. These SO-miRNAs were up-regulated during differentiation and the host mRNAs were down-regulated, but again there was no change in inclusion ratio of the SO-miRNA exons. Interestingly, Drosha silencing increased nascent RNA density, on chromatin, downstream from SO-miRNA exons. Overall our data suggest a novel mechanism for regulating gene expression in which MPC-dependent cleavage of SO-miRNA exons could cause premature transcriptional termination of coding genes rather than affecting alternative splicing.

Association of Radial Artery Graft vs Saphenous Vein Graft With Long-term Cardiovascular Outcomes Among Patients Undergoing Coronary Artery Bypass Grafting: A Systematic Review and Meta-analysis.

Importance: Observational studies have suggested that the use of radial artery grafts for coronary artery bypass grafting may improve clinical outcomes compared with the use of saphenous vein grafts, but this has not been confirmed in randomized trials. Objective: To compare clinical outcomes between patients receiving radial artery vs saphenous vein grafts for coronary artery bypass grafting after long-term follow-up. Design, Setting, and Participants: Patient-level pooled analysis comparing radial artery vs saphenous vein graft in adult patients undergoing isolated coronary artery bypass grafting from 5 countries (Australia, Italy, Serbia, South Korea, and the United Kingdom), with enrollment from 1997 to 2009 and follow-up completed in 2019. Interventions: Patients were randomized to undergo either radial artery (n = 534) or saphenous vein (n = 502) grafts for coronary artery bypass grafting. Main Outcomes and Measures: The primary outcome was a composite of death, myocardial infarction, or repeat revascularization and the secondary outcome was a composite of death or myocardial infarction. Results: A total of 1036 patients were randomized (mean age, 66.6 years in the radial artery group vs 67.1 years in the saphenous vein group; 376 [70.4%] men in the radial artery group vs 351 [69.9%] in the saphenous vein group); 942 (90.9%) of the originally randomized patients completed 10 years of follow-up (510 in the radial artery group). At a median (interquartile range) follow-up of 10 (10-11) years, the use of the radial artery, compared with the saphenous vein, in coronary artery bypass grafting was associated with a statistically significant reduction in the incidence of the composite outcome of death, myocardial infarction, or repeat revascularization (220 vs 237 total events; 41 vs 47 events per 1000 patient-years; hazard ratio, 0.73 [95% CI, 0.61-0.88]; P < .001) and of the composite of death or myocardial infarction (188 vs 193 total events; 35 vs 38 events per 1000 patient-years; hazard ratio, 0.77 [95% CI, 0.63-0.94]; P = .01). Conclusions and Relevance: In this individual participant data meta-analysis with a median follow-up of 10 years, among patients undergoing coronary artery bypass grafting, the use of the radial artery compared with the saphenous vein was associated with a lower risk of a composite of cardiovascular outcomes.

Sarcomas of the mandible.

INTRODUCTION: Sarcomas of the mandible are extremely rare tumors, with osteosarcoma being the most common, followed by Ewing's sarcoma MATERIALS AND METHODS: A retrospective review of the clinical records, imaging studies, and pathology slides of patients with sarcoma of the mandible at a Tertiary Care Cancer Center from 1998 to 2014 was undertaken. The impact of neoadjuvant chemotherapy and postoperative radiotherapy with or without chemotherapy was studied, and factors impacting upon local control and disease-specific survival were analyzed. RESULTS: Twenty-two patients were treated over the study period, comprising of 15 males and seven females. External swelling, intraoral growth, or facial numbness were the presenting symptoms. Eighteen patients had osteosarcoma and four had the Ewing's sarcoma. Nine patients received neoadjuvant chemotherapy. All but one patient underwent surgery. Eleven had negative margins, with 90% recurrence-free survival at 3 years, compared to 10 with positive or close margins, leading to 67% recurrence-free survival. None of the patients receiving neoadjuvant chemotherapy developed recurrence and all were alive at 3 years. The impact of postoperative radiotherapy or adjuvant chemotherapy was not statistically significant. CONCLUSIONS: Wide surgical resection with negative margins remains the hallmark of surgical treatment.

Oral rehabilitation for patients with marginal and segmental mandibulectomy: A retrospective review of 111 mandibular resection prostheses.

STATEMENT OF PROBLEM: Treatment and timing considerations for patients seeking oral rehabilitation after marginal or segmental mandibulectomy (with osseous reconstruction) are not well understood. PURPOSE: The purpose of this retrospective review study was to report the type and timing of oral rehabilitation for mandibular defects without discontinuity and to describe additional treatment considerations for rehabilitation. MATERIAL AND METHODS: The records were reviewed of all patients who received a mandibular resection prosthesis after marginal mandibulectomy, marginal mandibulectomy with fasciocutaneous free-flap reconstruction, and segmental mandibulectomy with fibula free-flap reconstruction between 2000 and 2017 in the tertiary cancer care institution. Patients not treated by the Dental Service in the institution were excluded. The specific type of rehabilitation was noted, as was the time interval between primary surgery and prosthesis delivery. RESULTS: During the study period, 111 consecutive patients were treated by the Memorial Sloan Kettering Cancer Center Dental Service for mandibular rehabilitation. Forty-three patients underwent marginal mandibulectomy, 9 patients underwent marginal mandibulectomy with fasciocutaneous free-flap reconstruction, and 59 patients underwent segmental mandibulectomy with fibula free-flap reconstruction. Most patients in all 3 groups received mandibular resection prostheses without the use of endosseous implants. Only 4 (8%) patients who had undergone marginal mandibulectomy underwent endosseous implant placement, all of which followed marginal mandibulectomy in anterior mandibular segments without free-flap reconstruction. Patients who underwent marginal mandibulectomy with fasciocutaneous free-flap reconstruction were only restored with removable mandibular resection prostheses, and none had endosseous implants. In patients who underwent segmental mandibulectomy, 13 (22%) were rehabilitated with endosseous implants. The majority in this cohort (>50%) received radiation therapy as part of their treatment. The median time to oral rehabilitation was 8 months after marginal mandibulectomy, 14 months after marginal mandibulectomy with fasciocutaneous free-flap reconstruction, and 12 months after segmental mandibulectomy with fibula free-flap reconstruction. CONCLUSIONS: Timing for oral rehabilitation may differ depending on the treatment modality followed for mandibular tumors in the patient with oral cancer. However, most patients in this cohort underwent rehabilitation with removable mandibular resection prostheses regardless of the timing of care. Endosseous implants were used infrequently, but research is needed to better understand their potential role and indication in the patient with oral cancer.

Oral rehabilitation following fasciocutaneous free-flap reconstruction: A retrospective study.

AIM: The aim of this study is to retrospectively, observe a consecutive series of patients with segmental mandibulectomy defects reconstructed with fasciocutaneous free flaps and mandibular resection prostheses, and to review treatment concepts for the management of such patients. SETTINGS AND DESIGN: Observational study done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. MATERIALS AND METHODS: Records were reviewed of all patients who had fasciocutaneous free-flap reconstruction and fabrication of mandibular resection prostheses following segmental mandibulectomy between 2000 and 2017 at a tertiary cancer center. Mandibular resection prosthesis fabrication interval data, as well as follow-up interval data, were recorded. STATISTICAL ANALYSIS USED: Descriptive statistics. RESULTS: Twenty-one consecutive patients had mandibular resection prostheses fabricated following segmental mandibulectomy and fasciocutaneous free-flap reconstruction during the study. The median time for mandibular resection prosthesis delivery following surgery was 9 months (range 4-41 months). There was a median of two-follow-up visits (range 0-4) within the first 90 days of mandibular resection prosthesis delivery. CONCLUSIONS: Oral rehabilitation with mandibular resection prosthesis following segmental mandibulectomy and fasciocutaneous free-flap reconstruction is an attainable treatment goal for the oncologic patient. Reviewing the proposed course of care is helpful for patient management.

Oral rehabilitation of the cancer patient: A formidable challenge.

Rehabilitation of oral functions following surgery on the jaws is a goal that is often difficult to achieve. Removable dentures supported by remaining teeth or gum are often unstable and seldom satisfactory. On the other hand, endosseous (dental) implants offer a mechanism to provide stability to the dentures. This review, discusses factors related to the tumor, patient, treatment, and physicians which impact upon the feasibility and success of dental implants in patients with oral cancer.

Gauging the response to cardiac resynchronization therapy: The important interplay between predictor variables and definition of a favorable outcome.

AIMS: Selection of patients who are viable candidates for cardiac resynchronization therapy (CRT), prediction of the response to CRT as well as an optimal definition of a favorable response, all require further exploration. The purpose of this study was to evaluate the interplay between the prediction of the response to CRT and the definition of a favorable outcome. METHODS: Seventy patients who received CRT were included. All patients met current guideline criteria for CRT. Forty-three echocardiographic parameters were evaluated before CRT and at 1, 3, 6, and 12 months. M-mode, 2D echocardiography, and Doppler imaging were used to quantify left ventricular (LV) systolic and diastolic function, mitral regurgitation, right ventricular systolic function, pulmonary artery pressure, and myocardial mechanical dyssynchrony. The following definitions of a favorable CRT response were used: left ventricular ejection fraction (LVEF) improvement more >5% acutely following CRT, LVEF improvement >20% at 12-month follow-up, and a LV end-systolic volume (LVESV) decrease >15% at 12-month follow-up. RESULTS: For the LVEF improvement >5%, the best predictor was isovolumetric relaxation time (IVRT; P=.035). For improvement of LVEF >20%, the best predictors were left ventricular stroke index (LVSI; P=.044) and left ventricular fractional shortening (LVFS; P=.031). For the drop in left ventricular systolic volume (LVESV >15%), the best predictor was septal-to-lateral wall delay (ΔT) (P=.043, RR=1.023, 95% CI for RR=1.001-1.045). CONCLUSION: The definition of a favorable CRT response influenced the optimal predictor variable(s). Standardization of defining a favorable response to CRT is needed to guide clinical decision making processes.

Consecutive Observational Study to Validate EuroSCORE II Performances on a Single-Center, Contemporary Cardiac Surgical Cohort.

OBJECTIVE: To compare and validate the original EuroSCORE risk stratification models with the renewed EuroSCORE II model in a contemporary cardiac surgical practice. DESIGN: A consecutive observational study to validate EuroSCORE II performances, conducted as retrospective analysis of prospectively collected data. SETTING: A tertiary university institute for cardiovascular diseases. PARTICIPANTS: Adult patients undergoing cardiac surgery between January and December 2012. METHODS: One thousand eight hundred sixty-four consecutive patients were scored preoperatively using additive and logistic EuroSCORE as well as EuroSCORE II. The discriminative power of the EuroSCORE models was tested by calculating the area under the receiver operating characteristic curve (AUC). The calibration of the models was assessed by Hosmer-Lemeshow statistics and with observed-to-expected mortality ratio. MEASUREMENTS AND MAIN RESULTS: The in-hospital overall mortality was 3.65%, with predicted mortalities according to additive EuroSCORE, logistic EuroSCORE, and EuroSCORE II of 5.14%, 6.60%, and 3.51%, respectively. The observed-to-expected (O/E) mortality ratio confirmed good calibration for the entire cohort only for EuroSCORE II (1.05, 95% confidence interval 0.81 - 1.29). Hosmer-Lemeshow test confirmed overall good calibration only for additive EuroSCORE (p = 0.129). The EuroSCORE II confirmed very good discriminatory power for a prolonged intensive care unit (ICU) stay of>2 days and>5 days (AUCs>0.75). Acceptable discriminatory power was confirmed for a prolonged postoperative stay of>7 days and>12 days (AUCs>0.70). CONCLUSION: EuroSCORE II confirmed very good discriminatory capacity, good calibration ability (O/E mortality ratio), and good capability to predict prolonged ICU and postoperative stays in a contemporary patient cohort undergoing cardiac surgery.

STAT3 signaling is activated preferentially in tumor-initiating cells in claudin-low models of human breast cancer.

In breast cancer, a subset of tumor-initiating cells (TIC) or "cancer stem cells" are thought to be responsible for tumor maintenance, treatment resistance, and disease recurrence. While current breast cancer stem cell markers (e.g., CD44(high) /CD24(low/neg) , ALDH positive) have allowed enrichment for such cells, they are not universally expressed and may actually identify distinct TIC subpopulations in the same tumor. Thus, additional markers of functional stem cells are needed. The STAT3 pathway is a critical regulator of the function of normal stem cells, and evidence is accumulating for its important role in breast cancer stem cells. However, due to the lack of a method for separating live cells based on their level of STAT3 activity, it remains unknown whether STAT3 functions in the cancer stem cells themselves, or in surrounding niche cells, or in both. To approach this question, we constructed a series of lentiviral fluorescent (enhanced green fluorescent protein, EGFP) reporters that enabled flow cytometric enrichment of cells differing in STAT3-mediated transcriptional activity, as well as in vivo/in situ localization of STAT3 responsive cells. Using in vivo claudin-low cell line xenograft models of human breast cancer, we found that STAT3 signaling reporter activity (EGFP(+) ) is associated with a subpopulation of cancer cells enriched for mammosphere-forming efficiency, as well as TIC function in limiting dilution transplantation assays compared to negative or unsorted populations. Our results support STAT3 signaling activity as another functional marker for human breast cancer stem cells thus making it an attractive therapeutic target for stem-cell-directed therapy in some breast cancer subtypes.

Workaholism, work engagement, and burnout among academics in Montenegro: A psychometric network approach.

BACKGROUND: The academic environment is known for its high demands in research, teaching, and administration, that along with increasing publish or perish culture can lead to reduced psychological well-being and mental health issues. OBJECTIVE: This study aimed to investigate the associations between workaholism, work engagement, and burnout among academics in Montenegro. METHODS: A cross-sectional design was used to develop anonymous online survey. Data was collected from 131 participants employed as teaching and research staff at public and private universities. To measure the variables of interest we used: ultra-short Utrecht Work Engagement Scale (UWES-3), the work-related burnout subscale from the Copenhagen Burnout Inventory (CBI-7) and the Dutch Work Addiction Scale (DUWAS-10). Psychometric network analysis was employed to examine the relationships among variables. RESULTS: The findings revealed two distinct clusters: the first containing the dimensions of work engagement and the second containing burnout and the dimensions of workaholism. The two clusters were connected with the dimensions of dedication - burnout having the strongest edge (-0.25 and -0.40). In the cross-sample network the strongest connection was burnout -working excessively (.35). No significant differences in network density (0.80 (12/15 edges)) and global strength (p = 0.159) in the networks of public and private universities were found. CONCLUSION: Results of the network centrality and the edge strength analyses suggest that the interventions focused at increasing dedication while not fostering a work environment that encourages working excessively might be the key to preventing and reducing burnout in academia across contexts of public and private universities.

Calcified amorphous tumor of the posterior mitral annulus.

A 73-year-old male with a history of hypertension, congenital kidney aplasia, status post-myocardial infarction, stroke, and chronic renal insufficiency was admitted to our institute due to coronary artery bypass grafting. Preoperative echocardiogram revealed a 15 × 7 mm mass arising near the posterior mitral annulus. Following the coronary artery bypass grafting, the left atrial cavity was explored using a 30° endoscope. The irregular peduncular calcified tumorous mass was revealed on the annulus of the posterior cusp, near the posteromedial commissure. The mass protruded into the left ventricle. The tumor mass was totally resected, and intraoperative transesophageal echocardiography did not register any residual tumor mass. Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-024-01688-8.

Influence of Thyroglobulin (Tg) Autoantibodies on Tg levels Measured by Different Methodologies: (IMA, LC-MS/MS and RIA).

CONTEXT: Serum thyroglobulin (Tg) measured by Immunometric assays (IMA) is prone to underestimation due to Tg autoantibody (TgAb) interference, often prompting reflex Tg measurement by liquid chromatography/tandem mass spectrometry (MS) or radioimmunoassay (RIA). OBJECTIVE: IMA, MS and RIA methodologies were used to measure serum Tg in TgAb-negative (TgAb-) and TgAb-positive (TgAb+) patients with either distant metastatic thyroid cancer (DTC) or hyperthyroidism (HY) - patients in whom a detectable serum Tg would be expected. CONCLUSIONS: 1) Between-method Tg variability necessitates method continuity when monitoring the Tg trends of TgAb- DTC patients. 2) The presence and concentration of TgAb appeared to have a lowering effect on serum Tg measured by all methodologies (IMA, MS and RIA). 3) Since the reliability of Tg measured in the presence of TgAb is often uncertain, the TgAb trend (measured by the same method) may be a useful surrogate DTC tumor marker.

DNA Mutational and Copy Number Variation Profiling of Primary Craniofacial Osteosarcomas by Next-Generation Sequencing.

BACKGROUND: Craniofacial osteosarcomas (CFOS) are uncommon malignant neoplasms of the head and neck with different clinical presentation, biological behavior and prognosis from conventional osteosarcomas of long bones. Very limited genetic data have been published on CFOS. METHODS: In the current study, we performed comprehensive genomic studies in 15 cases of high-grade CFOS by SNP array and targeted next generation sequencing. RESULT: Our study shows high-grade CFOS demonstrate highly complex and heterogenous genomic alterations and harbor frequently mutated tumor suppressor genes TP53, CDKN2A/B, and PTEN, similar to conventional osteosarcomas. Potentially actionable gene amplifications involving CCNE1, AKT2, MET, NTRK1, PDGFRA, KDR, KIT, MAP3K14, FGFR1, and AURKA were seen in 43% of cases. GNAS hotspot activating mutations were also identified in a subset of CFOS cases, with one case representing malignant transformation from fibrous dysplasia, suggesting a role for GNAS mutation in the development of CFOS. CONCLUSION: High-grade CFOS demonstrate highly complex and heterogenous genomic alterations, with amplification involving receptor tyrosine kinase genes, and frequent mutations involving tumor suppressor genes.

Mastering the Best Practices: A Comprehensive Look at the European Guidelines for Cardiopulmonary Bypass in Adult Cardiac Surgery.

The successful outcome of a cardiac surgery procedure is significantly dependent on the management of cardiopulmonary bypass (CPB). Even if a cardiac operation is technically well-conducted, a patient may suffer CPB-related complications that could result in severe comorbidities, reduced quality of life, or even death. However, the role of clinical perfusionists in perioperative patient care, which is critical, is often overlooked. Therefore, the European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Cardiothoracic Anaesthesiology (EACTA), and the European Board of Cardiovascular Perfusion (EBCP) have agreed to develop joint clinical practice guidelines (CPGs) for CPB due to its significant impact on patient care and significant variations in practice patterns between countries. The European guidelines, based on the EACTS standardized framework for the development of CPGs, cover the entire spectrum of CPB management in adult cardiac surgery. This includes training and education of clinical perfusionists, machine hardware, disposables, preparation for initiation of CPB, a complete set of procedures during CPB to help maintain end-organ function and anticoagulation, weaning from CPB, and the gaps in evidence and future research directions. This comprehensive coverage ensures that all aspects of CPB management are addressed, providing clinicians with a standardized approach to CPB management based on the latest evidence and best practices. To ensure better integration of these evidence-based recommendations into daily practice, this review aims to provide a general understanding of guideline development and an overview of essential treatment recommendations for CPB management.

Difference in immune responses to Candida albicans in two inbred strains of male rats.

OBJECTIVE: To investigate the influence of strain differences in immune response on the pathogenesis of oral candidiasis in Dark Agouti (DA) and Albino Oxford (AO) inbred strains of rats. DESIGN: Seventy male 8-weeks old DA and AO rats were inoculated with Candida albicans to induce three different experimental models of oral candidiasis, one immunocompetent and two immunocompromised models. The animals were sacrificed after 16 days from the beginning of the experiment followed by collecting the samples of the tongue dorsum and blood for histopathological (PAS and H&E staining), immunohistochemical, qRT-PCR, and oxidative stress analyses. RESULTS: Histopathological and immunohistochemical analyses revealed lower levels of epithelial colonization, epithelial damage, and inflammatory infiltration in DA compared to AO strain of rats. DA rats had fewer CD45, CD68, and CD3 positive cells but more HIS 48 positive cells than AO rats. The expressions of IL-1ß, TNFα, IFN-γ, IL-10 and TGF-ß1 were consistently higher in DA strain across all experimental models. However, the expressions of IL-4 and IL-17 differed inconsistently between DA and AO strain in various experimental models. Strain differences were observed in levels of prooxidative hydrogen peroxide and lipid peroxidation, with higher levels presented in AO rats compared to DA rats, while antioxidative parameters presented little yet inconsistent difference between strains. CONCLUSION: DA strain of rats consistently presented lower susceptibility to oral infection with C. albicans compared to AO strain with robust Th1/Th17 immune response indicating the importance of the genetic background on the development of oral candidiasis.