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The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug’s adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo , including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

Most breast cancer patients die of non-cancer causes. The risk of death from heart disease, a leading cause of death, is unknown. The aim of this study is to characterize the long-term risk of fatal heart disease in breast cancer patients. This retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database. Standard mortality ratios (SMR) were calculated for breast cancer patients diagnosed from 1992 to 2014. Patients were stratified by receipt of radiotherapy and/or chemotherapy, disease laterality, and diagnosis era. Hazard ratios (HRs) and odds ratios (ORs) were calculated to compare the risk of death from heart disease among other breast cancer patients. There were 1,059,048 patients diagnosed with breast cancer from 1992 to 2014, of which 47,872 (4.6%) died from heart disease. The SMR for death from heart disease at 10+ years for patients who received only radiotherapy was 2.92 (95% CI 2.81-3.04, < 0.001) and in patients who received only chemotherapy was 5.05 (95% CI 4.57-5.55, < 0.001). There was no statistically significant difference in SMR for death from heart disease for left-sided vs. right-sided disease. At 10+ years, heart disease made up 28% of deaths from non-primary cancer. HRs and ORs showed that the risk of death from heart disease was highest in patients older than 70 years of age and with longer follow-up. The risk of fatal heart disease was highest in older breast cancer patients with longer follow-up (i.e., >5-10 years) and who received chemotherapy. These patients should be referred to cardio-oncology clinics to mitigate this risk.

Catheter-related deep venous thrombosis (CR-DVT) is a common complication of central venous catheters, however optimal prophylactic and treatment strategies have yet to be fully defined. While the use of anticoagulation for CR-DVT prophylaxis is not routinely recommended, current available data offer heterogeneous results due to small sample size, non-uniform study design, and varying comorbid conditions. Available guidelines for the treatment of CR-DVT generally recommend a limited duration of anticoagulation after catheter removal. If ongoing use is required and the device remains functional, guidelines support anticoagulation throughout the time the catheter remains in place. It is worth acknowledging that data guiding these recommendations is largely derived from observational studies of upper extremity CR-DVT, along with randomized trials of anticoagulation in patients with lower extremity DVT. Therefore, large, randomized controlled trials are desperately needed to define optimal management, especially in patients who are at high risk for bleeding. This review explores the epidemiology and risk factors of CR-DVT, diagnostic, prophylactic and treatment strategies, guideline recommendations, and future advances in the field, including the introduction of novel anticoagulants. With current available evidence, we also conclude with an individualized approach to preventing and managing CR-DVT to assist clinicians who are faced with this common clinical scenario. Graphical abstract Algorithm for the prevention and treatment of catheter-related DVT. Abbreviations: DVT, deep venous thrombosis; PICC, peripherally inserted central catheter; CVC, central venous catheter; VTE, venous thromboembolism; CR-DVT, catheter-related deep venous thrombosis; ISTH, International Society on Thrombosis & Haemostasis; SVC, superior vena cava Key points Treatment guidelines for central catheter-associated venous thrombosis broadly recommend therapeutic anticoagulation either for a defined period of time or throughout the duration of catheter use if it remains in place, without other complication, and necessary. Prophylaxis for central venous catheter-related upper extremity thrombosis is not routinely recommended. Multiple risk factors can predispose to catheter-related thrombosis and well validated risk prediction tools are still needed. Larger randomized trials are needed to guide prophylaxis and treatment recommendations.

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs. HDI benefits as measured by the hazard ratios (HR) in E1684 (vs. observation), E1690 (vs. observation), and E1694 (vs. vaccine) trials were estimated at 0.61, 0.78, and 0.67 (RFS) and 0.67, 1.0, and 0.72 (OS) when first reported with lesser estimates on later updates. Pegylated IFNα (peg-IFN) as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma significantly reduced the risk of relapse (HR 0.87) with no impact on OS. More recently (EORTC 18071), ipilimumab at the high dose of 10 mg/kg was shown to significantly improve RFS (HR 0.76) and OS (HR 0.72) of stage III melanoma patients but at a significant cost in terms of immune-related toxicities. Ongoing adjuvant studies are testing ipilimumab at 3 or 10 mg/kg versus HDI (E1609) and the anti-PD-1 antibodies nivolumab (CheckMate 238) and pembrolizumab (KEYNOTE-054 and S1404).

Percutaneous patent ductus arteriosus (PDA) stenting is a therapeutic modality in patients with duct-dependent pulmonary circulation with reported success rates from 80-100%. The current study aims to assess the outcome and the indicators of success for PDA stenting in different ductal morphologies using various approaches. A prospective cohort study from a single tertiary center presented from January 2018 to December 2019 that included 96 consecutive infants with ductal-dependent pulmonary circulation and palliated with PDA stenting. Patients were divided according to PDA origin into 4 groups: Group 1: PDA from proximal descending aorta, Group 2: from undersurface of aortic arch, Group 3: opposite the subclavian artery, Group 4: opposite the innominate/brachiocephalic artery. The median age of patients was 22 days and median weight was 3 kg. The procedure was successful in 78 patients (81.25%). PDA was tortuous in 70 out of 96 patients. Femoral artery was the preferred approach in Group 1 (63/67), while axillary artery access was preferred in the other groups (6/11 in Group 2, 11/17 in Group 3, 1/1 in Group 4, P <0.0001). The main cause of procedural failure was inadequate parked coronary wire inside one of the branch of pulmonary arteries (14 cases; 77.7%), while 2 cases (11.1%) were complicated by acute stent thrombosis, and another 2 cases with stent dislodgment. Other procedural complications comprised femoral artery thrombosis in 7 cases (7.2%). Patients with straight PDA, younger age at procedure and who had larger PDA at pulmonary end had higher odds for success (OR = 8.01, 2.94, 7.40, CI = 1.011-63.68, 0.960-0.99, 1.172-7.40,respectively, P = 0.048, 0.031,0.022 respectively). The approach for PDA stenting and hence the outcome is markedly determined by the PDA origin and morphology. Patients with straight PDA, younger age at procedure and those who had relatively larger PDA at the pulmonary end had better opportunity for successful procedure.

Most animals possess taste receptors neurons detecting potentially noxious compounds. In humans, the ligands which activate these neurons define a sensory space called \"bitter\". By extension, this term has been used in animals and insects to define molecules which induce aversive responses. In this review, based on our observations carried out in Drosophila, we examine how bitter compounds are detected and if bitter-sensitive neurons respond only to molecules bitter to humans. Like most animals, flies detect bitter chemicals through a specific population of taste neurons, distinct from those responding to sugars or to other modalities. Activating bitter-sensitive taste neurons induces aversive reactions and inhibits feeding. Bitter molecules also contribute to the suppression of sugar-neuron responses and can lead to a complete inhibition of the responses to sugar at the periphery. Since some bitter molecules activate bitter-sensitive neurons and some inhibit sugar detection, bitter molecules are represented by two sensory spaces which are only partially congruent. In addition to molecules which impact feeding, we recently discovered that the activation of bitter-sensitive neurons also induces grooming. Bitter-sensitive neurons of the wings and of the legs can sense chemicals from the gram negative bacteria, Escherichia coli, thus adding another biological function to these receptors. Bitter-sensitive neurons of the proboscis also respond to the inhibitory pheromone, 7-tricosene. Activating these neurons by bitter molecules in the context of sexual encounter inhibits courting and sexual reproduction, while activating these neurons with 7-tricosene in a feeding context will inhibit feeding. The picture that emerges from these observations is that the taste system is composed of detectors which monitor different \"categories\" of ligands, which facilitate or inhibit behaviors depending on the context (feeding, sexual reproduction, hygienic behavior), thus considerably extending the initial definition of \"bitter\" tasting.

Introduction In recent years, the medical community has grown increasingly alarmed by the escalating rates of carbapenem resistance - a global concern that is also affecting the United Arab Emirates (UAE). This rise in antibiotic resistance poses a significant challenge to healthcare systems and necessitates urgent and comprehensive research. The primary objective of this study is to investigate the factors that influence the prognosis and outcomes of bacteremia caused by carbapenem-resistant Enterobacterales (CRE), managed with a combination of ceftazidime-avibactam (CAZ-AVI) and aztreonam (ATM). Understanding the determinants of treatment success may provide valuable insights into improving patient care and outcomes. Methods This retrospective observational chart review was conducted at Tawam Hospital, Al Ain, from 2020 to 2023. Seventeen adult patients (aged >18 years) with confirmed CRE bacteremia who received combination therapy with CAZ-AVI and ATM were included. Data were extracted from the SEHA electronic medical records, including demographics, clinical features, laboratory findings, and outcomes such as ICU admission, in-hospital mortality, and length of stay. Statistical analyses were performed using Excel, Meta-Chart, and SkyBlue Statistics. Given the small sample size, descriptive statistics were prioritized, and chi-square and unpaired t-tests were used to explore associations, recognizing limitations in statistical power. Results The incidence of CRE bacteremia treated with CAZ-AVI and ATM increased over the study period, with the highest number of cases recorded in 2023. Antimicrobial resistance remained consistently high across both beta-lactam and non-beta-lactam classes. The overall in-hospital mortality rate was 29.4%, with long-term four-year mortality reaching 53%. The median length of hospital stay was 19 days, and 17.6% of patients required intensive care. Poor outcomes were primarily associated with immunosuppression, prior hospitalizations, and multiple comorbidities. Conclusion This study highlights the increasing clinical burden of CRE bacteremia in the UAE. By identifying key prognostic factors and reporting high mortality and prolonged hospital stays despite combination therapy, it underscores the urgent need for timely intervention, improved antimicrobial stewardship, and enhanced diagnostic capacity. These findings contribute valuable regional data to the global effort to curb antimicrobial resistance.

BackgroundSeveral reports of unheeded complications secondary to the current mass international rollout of SARS-COV-2 vaccines, one of which is myocarditis occurring with the FDA fully approved vaccine, Pfizer, and others.Main body of the abstractCertain miRNAs (non-coding RNA sequences) are involved in the pathogenesis in viral myocarditis, and those miRNAs are interestingly upregulated in severe COVID-19. We hypothesize that the use of mRNA-based vaccines may be triggering the release of host miRNAs or that trigger the occurrence of myocarditis. This is based on the finding of altered host miRNA expression promoting virus-induced myocarditis.Short conclusionIn conclusion, miRNAs are likely implicated in myocarditis associated with mRNA vaccines. Our hypothesis suggests the use of miRNA as a biomarker for the diagnosis of mRNA vaccine-induced myocarditis. Additionally, the interplay between viral miRNA and the host immune system could alter inflammatory profiles, hence suggesting the use of therapeutic inhibition to prevent such complications.