K-ATP channel gene expression is induced by urocortin and mediates its cardioprotective effect

Background-Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.Methods and Results-We have analyzed global changes in gone expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K-ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.Conclusions-This is, to our knowledge, the first report of the altered expression of a K-ATP. channel subunit induced by a cardioprotective agent and demonstrates that K-ATP, channel opening is essential for the effect of this novel cardioprotective agent

Organic aerosol and global climate modelling: a review

The present paper reviews existing knowledge with regard to Organic Aerosol (OA) of importance for global climate modelling and defines critical gaps needed to reduce the involved uncertainties. All pieces required for the representation of OA in a global climate model are sketched out with special attention to Secondary Organic Aerosol (SOA): The emission estimates of primary carbonaceous particles and SOA precursor gases are summarized. The up-to-date understanding of the chemical formation and transformation of condensable organic material is outlined. Knowledge on the hygroscopicity of OA and measurements of optical properties of the organic aerosol constituents are summarized. The mechanisms of interactions of OA with clouds and dry and wet removal processes parameterisations in global models are outlined. This information is synthesized to provide a continuous analysis of the flow from the emitted material to the atmosphere up to the point of the climate impact of the produced organic aerosol. The sources of uncertainties at each step of this process are highlighted as areas that require further studies

Targeted intraoperative radiotherapy tumour bed boost during breast conserving surgery after neoadjuvant chemotherapy

Introduction: The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT). / Method: In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence free survival (LRFS), disease free survival (DFS), distant disease free survival (DDFS), breast-cancer mortality (BCM), non-breast-cancer mortality (NBCM) and overall mortality (OS) were compared. / Results: Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5-year Kaplan-Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events 96.7%(95%CI 87.5 – 99.2), EBRT 9 events 81.7% (95%CI 67.6 – 90.1), HR 0.19 (0.04 – 0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3 – 95.7), HR (not calculable), log rank p=0.015. The DDFS was: IORT 3 events, 95.1% (85.5-98.4), EBRT 12 events, 69.0% (49.1 – 82.4), HR 0.23 (0.06-0.80), log rank p=0.012. Conclusion: IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT Boost is superior to EBRT Boost

Systematic investigation of organochlorine pesticides and polychlorinated biphenyls blood levels in Greek children from the Rhea birth cohort suggests historical exposure to DDT and through diet to DDE

Data availability: Data will be made available on request.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S0160412024002721#s0090:~:text=Appendix%20A.-,Supplementary%20data,-Data%20availability .The blood levels of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) have been thoroughly investigated in Greek children from the Rhea birth cohort study. This investigation aimed to assess exposure levels, explore their possible relationship with children's age and sex, and indicate potential sources of exposure. Exposure patterns and common sources of PCBs and OCPs were analyzed using bivariate and multivariate statistics. A total of 947 blood samples from study participants were analyzed for OCP and PCB exposure, with 375 samples collected at 4 years old, 239 at 6.5 years old, and 333 at 11 years old. Elevated levels of DDE were observed in 6.5-year-old children compared to corresponding levels in other European countries. Higher levels of DDE were found in 4-year-old children, with the lowest concentrations in the 11-year-old group. The DDT/DDE ratio was consistently less than 1 among all the examined subjects. These results indicate exposure to DDT and DDE both in utero and through breastfeeding and dietary intake. For the entire cohort population, the highest concentration was determined for PCB 28, followed by PCBs 138, 153, and 180. The sum of the six indicator PCBs implied low exposure levels for the majority of the cohort population. Spearman correlations revealed strong associations between PCBs and OCPs, while principal component analysis identified two different groupings of exposure. DDE exhibited a correlation with a series of PCBs (153, 156, 163, 180), indicating a combined OCP-PCB source, and an anticorrelation with others (52, 28, 101), implying a separate and competing source.Hellenic Ministry of Health and the General Secretariat for Research and Innovation

Targeted intraoperative radiotherapy tumour bed boost during breast conserving surgery after neoadjuvant chemotherapy in HER2 positive and triple negative breast cancer

Introduction: Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumour bed boost after breast conserving surgery is well established for women with early breast cancer. A previous study from our group shows a beneficial effect of TARGIT-IORT on overall survival (OS) but not diseasefree survival (DFS) after neoadjuvant chemotherapy compared to an external boost suggesting a potential non-inferiority of TARGIT-IORT. In this study, we present results regarding the high-risk subset of patients (i.e. with triple negative (TN) and HER2 positive tumours) from this cohort. Method: In this non-randomized cohort study involving patients with HER2 positive (n= 28) and triple negative (n=42) tumours after NACT we compared outcomes of 40 patients with tumour bed boost applied with TARGIT IORT during lumpectomy versus 30 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Rates of DFS and OS were compared. Results: Median follow up was 49 months. In comparison of TARGIT-IORT vs. EBRT 5-year Kaplan- Meier estimates of OS showed no significant difference among patients with HER2 positive tumours (100% vs. 91.7%, log rank p = 0.22). The same was seen for DFS (83.3% vs. 77.0%, log rank p=0.38). The results for TN cases were similar (OS : 87.5% vs. 74.1%, log rank p=0.488; DFS 87.5% vs. 60%, log rank p=0.22). Conclusion: Although survival estimates trended towards favouring TARGIT-IORT, no significant differences could be observed and the significantly positive result for OS favoring TARGIT-IORT in the whole cohort of 116 patients could not be reproduced in this subset analysis of patients with TN and HER2 positive tumours. This may be contributable to the limited number of patients but may also indicate that effects seen in the whole cohort were mainly driven by ER and/or PR positive and HER2 negative tumours. Most importantly, non-inferiority of TARGIT-IORT as an intraoperative boost could be reproduced in these high-risk patients

Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy - a Subgroup Analysis of Hormone Receptor-Positive HER2-Negative Breast Cancer

INTRODUCTION: In a previous study our group showed a beneficial effect of targeted intraoperative radiotherapy (TARGIT-IORT) as an intraoperative boost on overall survival after neoadjuvant chemotherapy (NACT) compared to an external boost (EBRT). In this study we present the results of a detailed subgroup analysis of the hormone receptor (HR)-positive HER2-negative patients. METHODS: In this cohort study involving 46 patients with HR-positive HER2-negative breast cancer after NACT, we compared the outcomes of 21 patients who received an IORT boost to those of 25 patients treated with an EBRT boost. All patients received whole breast radiotherapy. RESULTS: Median follow-up was 49 months. Whereas disease-freesurvival and breast cancer-specific mortality were not significantly different between the groups, the 5-year Kaplan-Meier estimate of overall mortality was significantly lower by 21% with IORT, p = 0.028. Non-breast cancer-specific mortality was significantly lower by 16% with IORT, p = 0.047. CONCLUSION: Although our results have to be interpreted with caution, we have shown that the improved overall survival demonstrated previously could be reproduced in the HR-positive HER2-negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost

2'-O-methoxyethyl splice-switching oligos correct splicing from IVS2-745 β-thalassemia patient cells restoring HbA production and chain rebalance

\u3b2-thalassemia is a disorder caused by altered hemoglobin protein synthesis and affects individuals worldwide. Severe forms of the disease, left untreated, can result in death before the age of 3 years (1). The standard of care consists of chronic and costly palliative treatment by blood transfusion combined with iron chelation. This dual approach suppresses anemia and reduces iron-related toxicities in patients. Allogeneic bone marrow transplant is an option, but limited by the availability of a highly compatible HSC donor. While gene therapy is been explored in several trials, its use is highly limited to developed regions with centers of excellence and well-established healthcare systems (2). Hence, there remains a tremendous unmet medical need to develop alternative treatment strategies for \u3b2-thalassemia (3). Occurrence of aberrant splicing is one of the processes that affects \u3b2-globin synthesis in \u3b2-thalassemia. The (C>G) IVS-2-745 is a splicing mutation within intron 2 of the \u3b2-globin gene. It leads to an aberrantly spliced mRNA that incorporates an intron fragment. This results in an in-frame premature termination codon that inhibits \u3b2-globin production. Here, we propose the use of uniform 2'-O-methoxyethyl (2'-MOE) splice switching oligos (SSOs) to reverse this aberrant splicing in the pre-mRNA. With these lead SSOs we show aberrant to wild type splice switching. This switching leads to an increase of adult hemoglobin (HbA) up to 80% in erythroid cells from patients with the IVS-2-745 mutation. Furthermore, we demonstrate a restoration of the balance between \u3b2-like- and \u3b1-globin chains, and up to an 87% reduction in toxic \u3b1-heme aggregates. While examining the potential benefit of 2'-MOE-SSOs in a mixed sickle-thalassemic phenotypic setting, we found reduced HbS synthesis and sickle cell formation due to HbA induction. In summary, 2'-MOE-SSOs are a promising therapy for forms of \u3b2-thalassemia caused by mutations leading to aberrant splicing

A Measure-Theoretic Model for Collective Cell Migration and Aggregation

The aim of this paper is to present a measure-theoretic approach able to derive an Eulerian model of the dynamics of a cell population with a nite number of cells out of a microscopic Lagrangian description of the underlying cellular particle system. By looking at the spatial distribution of cells in terms of a time-evolving probability measure, rather than at individual cell paths, an ensemble representation of the cell colony is obtained, which can then result either in discrete, continuous, or hybrid approaches according to the spatial structure of such a probability measure. Remarkably, such an approach does not call for any assumption on the number of cells taken into account, thus providing consistency of the same modeling framework across all levels of representation. In addition, it is suitable to cope with the often ambiguous translation of microscopic arguments (i.e., cell dimensions and interaction radii) into macroscopic descriptions. The proposed approach, also extended to the case of multiple coexisting cell populations, is then tested with sample simulations that provide a useful sensitivity analysis of the model parameters

Fish Farms at Sea: The Ground Truth from Google Earth

In the face of global overfishing of wild-caught seafood, ocean fish farming has augmented the supply of fresh fish to western markets and become one of the fastest growing global industries. Accurate reporting of quantities of wild-caught fish has been problematic and we questioned whether similar discrepancies in data exist in statistics for farmed fish production. In the Mediterranean Sea, ocean fish farming is prevalent and stationary cages can be seen off the coasts of 16 countries using satellite imagery available through Google Earth. Using this tool, we demonstrate here that a few trained scientists now have the capacity to ground truth farmed fish production data reported by the Mediterranean countries. With Google Earth, we could examine 91% of the Mediterranean coast and count 248 tuna cages (circular cages >40 m diameter) and 20,976 other fish cages within 10 km offshore, the majority of which were off Greece (49%) and Turkey (31%). Combining satellite imagery with assumptions about cage volume, fish density, harvest rates, and seasonal capacity, we make a conservative approximation of ocean-farmed finfish production for 16 Mediterranean countries. Our overall estimate of 225,736 t of farmed finfish (not including tuna) in the Mediterranean Sea in 2006 is only slightly more than the United Nations Food and Agriculture Organization reports. The results demonstrate the reliability of recent FAO farmed fish production statistics for the Mediterranean as well as the promise of Google Earth to collect and ground truth data